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1
Yourno, J., P. Burkart, W. Mastropaolo, F. Lizzi, and A. Tartaglia. "Monocyte nonspecific esterase. Enzymologic characterization of a neutral serine esterase associated with myeloid cells." Journal of Histochemistry & Cytochemistry 34, no. 6 (June 1986): 727–33. http://dx.doi.org/10.1177/34.6.3457861.
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Monocytes contain a characteristic, prominent set of membrane-bound nonspecific esterases with a slightly acid isoelectric point. These esterases are also detected at modest levels in some granulocyte preparations. They are not apparent in lymphocytes. Among 18 fresh myeloid leukemias and myeloid leukemia cell lines, those of subtypes M4 (myelomonocytic) and M5 (monocytic) were strongly positive; some of subtypes M1-M3 (granulocytic) were moderately positive. The esterases were not detected among 32 fresh lymphoid leukemias and lymphoid leukemia and lymphoblast cell lines. The membrane-bound monocyte esterases, solubilized by treatment of monocyte preparations with nonionic detergent, were resolved by ion-exchange chromatography. The monocyte species account for 80-95% of the total nonspecific esterase activity of monocytes. The resolved enzymes behave as neutral serine carboxyl esterases and are highly sensitive to inhibition by diisopropylfluorophosphate (DFP) and also by sodium fluoride. Similar analysis of a lymphocyte preparation yielded no detectable monocyte esterases, but yielded numerous other forms which were generally resistant to inhibition by DFP and NaF. These nonspecific esterases are also present at background levels in monocytes. The resolution and characterization of the membrane-bound serine esterases from monocytes demonstrates the basis for the well-known cytochemistry of monocytes. The results are also crucial to the development of an immunologic surface marker test for myeloid cells and the study of monocyte membrane physiology.
2
Zachariae, C. O., A. O. Anderson, H. L. Thompson, E. Appella, A. Mantovani, J. J. Oppenheim, and K. Matsushima. "Properties of monocyte chemotactic and activating factor (MCAF) purified from a human fibrosarcoma cell line." Journal of Experimental Medicine 171, no. 6 (June 1, 1990): 2177–82. http://dx.doi.org/10.1084/jem.171.6.2177.
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A monocyte chemotactic and activating factor (MCAF) has been purified from TNF-stimulated 8387 human fibrosarcoma cell line-conditioned media. The purified MCAF showed microheterogeneity yielding two bands on SDS-PAGE analysis. Fibrosarcoma-derived MCAF specifically competed with THP-1 (a human monocytic cell line)-derived 125I-labeled MCAF in binding to human PBMC, whereas a similar basic heparin-binding leukocyte chemoattractant, IL-8, did not. The purified MCAF stimulated superoxide anion and N-acetyl beta-D glucosaminidase-releasing activity in human monocytes, as well as monocyte cytostatic augmenting activity against tumor cells and chemotactic activity for monocytes. When injected subcutaneously into Lewis rat ears, the purified human MCAF also induced considerable in vivo local monocyte infiltration beginning at 3 h and becoming maximal at 18 h. In conclusion, the data presented in this paper indicate that MCAF is a potent activator of monocytes as well as a monocyte recruitment factor that acts through receptors that are specific for this novel molecule. This novel cytokine might have an important role in tumor growth control due to its ability to attract and activate monocytes.
3
Schroff, RW, MM Farrell, RA Klein, HC Stevenson, and NL Warner. "Induction and enhancement by monocytes of antibody-induced modulation of a variety of human lymphoid cell surface antigens." Blood 66, no. 3 (September 1, 1985): 620–26. http://dx.doi.org/10.1182/blood.v66.3.620.620.
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Abstract We have previously reported that the addition of monocytes results in enhanced modulation of the T65 antigen when normal or leukemic lymphoid cells were cultured in vitro with the T101 monoclonal antibody. In the present investigation, we extend these findings to demonstrate that monocyte-enhanced modulation is a phenomenon that occurs with a variety of T and B lymphoid antigens identified by murine monoclonal antibodies. Two patterns of monocyte-enhanced modulation were observed: (1) augmentation by monocytes of existing antigen modulation by the T101 and anti-Leu-4 antibodies, and (2) induction by monocytes of previously unrecognized modulation with the anti-Leu-2 and anti-Leu-9 antibodies. Enhancement of modulation by monocytes was also detected with antibodies to surface IgM and HLA-DR antigens. Antigen modulation on lymphoid cell lines appeared to be more variable than on fresh cells, with or without monocytes. Monocyte-enhanced antigen modulation was not demonstrated with two monoclonal antibodies against solid tumors. Monocyte-enhanced modulation was shown to be dependent upon the Fc portion of the antibody, but independent of proteolytic or oxidative compounds released by monocytes. These findings indicate that the results obtained during in vitro studies of antigen modulation may vary with the source of cells and the extent to which monocytic cells are present. In addition, these findings suggest an enhanced role for Fc receptor-bearing cells of monocytic origin in antigen modulation following in vivo administration of monoclonal antibodies.
4
Schroff, RW, MM Farrell, RA Klein, HC Stevenson, and NL Warner. "Induction and enhancement by monocytes of antibody-induced modulation of a variety of human lymphoid cell surface antigens." Blood 66, no. 3 (September 1, 1985): 620–26. http://dx.doi.org/10.1182/blood.v66.3.620.bloodjournal663620.
Full textAbstract:
We have previously reported that the addition of monocytes results in enhanced modulation of the T65 antigen when normal or leukemic lymphoid cells were cultured in vitro with the T101 monoclonal antibody. In the present investigation, we extend these findings to demonstrate that monocyte-enhanced modulation is a phenomenon that occurs with a variety of T and B lymphoid antigens identified by murine monoclonal antibodies. Two patterns of monocyte-enhanced modulation were observed: (1) augmentation by monocytes of existing antigen modulation by the T101 and anti-Leu-4 antibodies, and (2) induction by monocytes of previously unrecognized modulation with the anti-Leu-2 and anti-Leu-9 antibodies. Enhancement of modulation by monocytes was also detected with antibodies to surface IgM and HLA-DR antigens. Antigen modulation on lymphoid cell lines appeared to be more variable than on fresh cells, with or without monocytes. Monocyte-enhanced antigen modulation was not demonstrated with two monoclonal antibodies against solid tumors. Monocyte-enhanced modulation was shown to be dependent upon the Fc portion of the antibody, but independent of proteolytic or oxidative compounds released by monocytes. These findings indicate that the results obtained during in vitro studies of antigen modulation may vary with the source of cells and the extent to which monocytic cells are present. In addition, these findings suggest an enhanced role for Fc receptor-bearing cells of monocytic origin in antigen modulation following in vivo administration of monoclonal antibodies.
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von Hundelshausen, Philipp, Rory R. Koenen, Markus Sack, Sebastian F. Mause, Wencke Adriaens, Amanda E. I. Proudfoot, Tilman M. Hackeng, and Christian Weber. "Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium." Blood 105, no. 3 (February 1, 2005): 924–30. http://dx.doi.org/10.1182/blood-2004-06-2475.
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AbstractThe chemokines platelet factor 4 (PF4) and RANTES (regulated on activation normal T cell expressed and secreted) are secreted by activated platelets and influence multiple cell types and biologic processes. For instance, PF4 inhibits progenitor cell proliferation and angiogenesis, while platelet-derived RANTES is involved in vascular recruitment of monocytes. However, little is known about functional interactions of PF4 and RANTES. Here we show that the presence of PF4 enhanced the arrest of RANTES-stimulated monocytes and monocytic cells on activated endothelial cells under flow conditions, while binding of PF4 to the monocyte surface was increased by RANTES. Both RANTES-triggered arrest and PF4 binding involved monocytic chondroitin sulfate. Ligand blots and surface plasmon resonance revealed a robust heterophilic interaction of PF4 with RANTES but not with RANTES variants defective in higher order oligomerization. The tetrameric mutant E26A bound to the monocyte surface without increasing PF4 binding, and monocyte arrest induced by E26A-RANTES was not enhanced by PF4. Stimulation of monocytes with supernatants of activated platelets triggered arrest involving RANTES and PF4, as shown by inhibition studies. Our results suggest that heterophilic interactions with PF4 require structural motifs important in RANTES oligomerization and amplify RANTES-triggered effects on monocyte adhesion. This may have implications for the modulation of inflammatory recruitment by platelet-derived chemokines.
6
Zawada, Adam M., Kyrill S. Rogacev, Björn Rotter, Peter Winter, Rolf-R. Marell, Danilo Fliser, and Gunnar H. Heine. "SuperSAGE evidence for CD14++CD16+ monocytes as a third monocyte subset." Blood 118, no. 12 (September 22, 2011): e50-e61. http://dx.doi.org/10.1182/blood-2011-01-326827.
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Abstract Monocytes are a heterogeneous cell population with subset-specific functions and phenotypes. The differential expression of CD14 and CD16 distinguishes classical CD14++CD16−, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes. Current knowledge on human monocyte heterogeneity is still incomplete: while it is increasingly acknowledged that CD14++CD16+ monocytes are of outstanding significance in 2 global health issues, namely HIV-1 infection and atherosclerosis, CD14++CD16+ monocytes remain the most poorly characterized subset so far. We therefore developed a method to purify the 3 monocyte subsets from human blood and analyzed their transcriptomes using SuperSAGE in combination with high-throughput sequencing. Analysis of 5 487 603 tags revealed unique identifiers of CD14++CD16+ monocytes, delineating these cells from the 2 other monocyte subsets. Gene Ontology (GO) enrichment analysis suggests diverse immunologic functions, linking CD14++CD16+ monocytes to Ag processing and presentation (eg, CD74, HLA-DR, IFI30, CTSB), to inflammation and monocyte activation (eg, TGFB1, AIF1, PTPN6), and to angiogenesis (eg, TIE2, CD105). In conclusion, we provide genetic evidence for a distinct role of CD14++CD16+ monocytes in human immunity. After CD14++CD16+ monocytes have earlier been discussed as a potential therapeutic target in inflammatory diseases, we are hopeful that our data will spur further research in the field of monocyte heterogeneity.
7
Surdacki, Andrzej, Joanna Sulicka, Mariusz Korkosz, Tomasz Mikołajczyk, Dorota Telesińska-Jasiówka, Ewa Klimek, Izabella Kierzkowska, Tomasz Guzik, and Tomasz K. Grodzicki. "Blood Monocyte Heterogeneity and Markers of Endothelial Activation in Ankylosing Spondylitis." Journal of Rheumatology 41, no. 3 (February 1, 2014): 481–89. http://dx.doi.org/10.3899/jrheum.130803.
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Objective.Ankylosing spondylitis (AS) is associated with excessive cardiovascular (CV) morbidity. Interactions between activated endothelium and monocytes precede atherosclerotic plaques. Our aim was to quantify blood monocyte subsets in relation to endothelial activation and inflammatory activity in subjects with AS who were free of clinical atherosclerotic CV disease.Methods.Markers of inflammation and endothelial activation were measured in 47 patients with AS receiving no disease-modifying antirheumatic drugs, and 22 healthy controls. Exclusion criteria included atherosclerotic CV disease and traditional risk factors. Flow cytometry was used to identify monocyte subsets: classical CD14++CD16−, intermediate CD14++CD16+, and nonclassical CD14+CD16++monocytes and to evaluate their expression of CD11b and CD11c.Results.Traditional risk factors were comparable among the groups, except for lower high-density lipoprotein cholesterol in AS (p = 0.007). Relative to controls, in subjects with AS counts of classical monocytes were higher (84.3 ± 5.4 vs 78.9 ± 5.3% of blood monocytes, p < 0.001) and nonclassical monocytes lower (2.9 ± 2.2 vs 5.5 ± 2.3%, p < 0.001). In AS we observed increased soluble intercellular adhesion molecule-1 [251 (224–293) vs 202 (187–230) ng/ml, p = 0.002], an endothelial ligand for monocytic β2-integrin CD11b/CD18. CD11b expression on all 3 monocyte subsets was elevated in 21 AS subjects with a Bath Ankylosing Spondylitis Disease Activity Index score ≥ 4 versus the remaining patients (p = 0.005–0.03). C-reactive protein, interleukin 6 (IL-6), and pentraxin-3 were increased in AS, in contrast to tumor necrosis factor-α and IL-18. IL-6 correlated with classical monocytes numbers in AS (r = 0.56, p < 0.0001) but not in the controls (r = 0.10, p = 0.65).Conclusion.Our findings suggest a contribution of immune dysregulation to enhanced monocyte-endothelial interactions in AS, especially in patients with active disease, which possibly can accelerate atherogenesis on a longterm basis.
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Jansen, J. H., J. C. Kluin-Nelemans, J. Van Damme, G. J. Wientjens, R. Willemze, and W. E. Fibbe. "Interleukin 6 is a permissive factor for monocytic colony formation by human hematopoietic progenitor cells." Journal of Experimental Medicine 175, no. 4 (April 1, 1992): 1151–54. http://dx.doi.org/10.1084/jem.175.4.1151.
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Since monocytes and macrophages that arise during the culture of bone marrow progenitor cells are potential sources of interleukin 6 (IL-6), we investigated whether auto- or paracrine production of this factor is involved in colony formation by normal hematopoietic progenitor cells. We added a polyclonal anti-IL-6 antiserum and a monoclonal anti-IL-6 antibody to cultures of monocyte- and T cell-depleted bone marrow cells. Colony formation was stimulated with granulocyte/monocyte-colony-stimulating factor (GM-CSF), monocyte-CSF, or IL-3. Addition of anti-IL-6 antibody resulted in decreased numbers of monocytic colonies to 40-50% of control values, whereas the numbers of granulocytic colonies were not altered. The inhibitory effect was preserved in cultures of CD34(+)-enriched bone marrow cells. As a second approach, we added a monoclonal antibody directed against the IL-6 receptor to cultures of monocyte- and T cell-depleted bone marrow cells. This antibody almost completely inhibited the growth of monocytic colonies, again without decreasing the number of granulocytic colonies. Finally, the importance of IL-6 in monocytopoiesis was demonstrated in serum-deprived bone marrow cultures: addition of exogenous IL-6 to cultures stimulated with GM-CSF resulted in increased numbers of monocytic colonies. Our results indicate that the permissive presence of IL-6 is required for optimal monocytic colony formation by bone marrow progenitor cells.
9
Oeth, Paul, Jin Yao, Sao-Tah Fan, and Nigel Mackman. "Retinoic Acid Selectively Inhibits Lipopolysaccharide Induction of Tissue Factor Gene Expression in Human Monocytes." Blood 91, no. 8 (April 15, 1998): 2857–65. http://dx.doi.org/10.1182/blood.v91.8.2857.2857_2857_2865.
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Expression of tissue factor (TF) by activated monocytes in several diseases leads to disseminated intravascular coagulation. Lipopolysaccharide (LPS)-induced monocyte TF expression is downregulated by the nuclear hormone all-trans retinoic acid (ATRA). In this study, we examined the mechanism by which ATRA inhibits monocyte TF expression. We show that ATRA selectively inhibited LPS induction of TF expression in human monocytes and monocytic THP-1 cells without affecting LPS induction of tumor necrosis factor-α (TNF-α) and interleukin-8 (IL-8). Inhibition of TF expression occurred at the level of transcription as determined by nuclear run-on. ATRA did not significantly alter the binding or functional activity of the transcription factors c-Fos/c-Jun and c-Rel/p65, which are required for LPS induction of the TF promoter in monocytic cells. In contrast to the ATRA inhibition of the endogenous TF gene, LPS induction of the cloned TF promoter was not inhibited by ATRA in transiently transfected THP-1 cells. Our results demonstrate that ATRA selectively inhibited LPS-induced TF gene transcription in human monocytic cells by a mechanism that does not involve repression of AP-1– or NF-κB–mediated transcription.
10
Park, In-Woo, Appakkudal R. Anand, and Jerome E. Groopman. "Molecular Characterization of the Cannabinoid-Mediated Migration of Monocytes." Blood 106, no. 11 (November 16, 2005): 3878. http://dx.doi.org/10.1182/blood.v106.11.3878.3878.
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Abstract 2-Arachidonoylglycerol (2-AG), an endogenous ligand for the cannabinoid receptors CB1 and CB2, functions as a chemokine for monocyte migration. However, the molecular mechanism of its chemotactic effects is not clear. We found, consistent with previous data, that 2-AG induces the migration of differentiated but not undifferentiated monocytic cells in a dose-dependent manner. We first asked whether the expression of cannabinoid receptors changed during monocytic differentiation. Treatment with 1,25-(OH)2vitamin D3, a potent inducer of monocyte differentiation, or with 2-AG did not alter the surface expression of the CB1 and CB2 receptors, indicating that signaling downstream of receptor ligation accounted for the observed effect on monocyte migration. In addition, treatment of differentiated monocytic cells with inhibitors for adenyl cyclase and rho kinase blocked the 2-AG-mediated migration, directly implicating these signaling molecules in monocyte motility. Upon eliminating the concentration gradient of 2-AG, the motility of the cells from the upper to lower compartment was sharply reduced, but not completely abrogated. This suggested that the chemotactic effect may not fully explain the observed change in cell migration. Of note, treatment of monocytes with 2-AG resulted in an enhanced secretion of the chemokines MCP-1 and IL-8. Moreover, exposure of the cells to 2-AG inhibited their migration towards MCP-1, while exposure to MCP-1 did not alter migration toward 2-AG. Taken together, our findings demonstrate that intracellular signaling cascades as well as induction of chemokine secretion contribute to the cannabinoid-mediated migration of monocytes.
11
Helset, E., T. Sildnes, and Z. S. Konopski. "Endothelin-1 Stimulates Monocytesin vitroto Release Chemotactic Activity Identified as Interleukin-8 and Monocyte Chemotactic Protein-1." Mediators of Inflammation 3, no. 2 (1994): 155–60. http://dx.doi.org/10.1155/s0962935194000207.
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In the present study we examined whether endothelin-1 stimulation of human monocytes causes release of chemotactic factors. It was found that monocytes released neutrophil- and monocyte-chemotactic activity in a dose- and time-dependent manner in response to ET-1. ET-1 did not show any chemotactic activity by itself. NCA was detected in monocyte supernatants in response to ET-1 (0.01–100 nM) after 1, 4, 8 and 24 h stimulation. MCA was detected only after 24 h stimulation with ET-1 (0.1–100 nM). Preincubation of the monocyte cultures with the lipoxygenase inhibitors nordihydroguaiaretic acid (10−4M) or diethylcarbamazine (10−9M) completely abolished the appearance of NCA and MCA. NCA was neutralized by > 75% using a polyclonal antibody against human interleuktn-8. The ET-1 induced release of IL-8 was confirmed by IL-8 ELISA. A monoclonal antibody against human monocyte chemotactic protein-1 neutralized MCA by > 80%. It is concluded that ET-1 stimulation of monocytesin vitrocauses release of neutrophil- and monocyte-chemotactic activity identified as IL-8 and MCP-I respectively. An intact lipoxygenase pathway is crucial for this effect of ET-1 to occur.
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Snipes, RG, KW Lam, RC Dodd, TK Gray, and MS Cohen. "Acid phosphatase activity in mononuclear phagocytes and the U937 cell line: monocyte-derived macrophages express tartrate-resistant acid phosphatase." Blood 67, no. 3 (March 1, 1986): 729–34. http://dx.doi.org/10.1182/blood.v67.3.729.729.
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Abstract Tartrate-resistant acid phosphatase (TRAcP) is used as a marker for osteoclasts, which are believed to be derived from phagocytic cells or phagocyte stem cell precursors. To further investigate the relationship between monocytic phagocytes and osteoclasts, acid phosphatase (AcP) activity was measured by three different techniques in human peripheral blood monocytes, monocyte-derived macrophages, and the U937 cell line. We found that cytochemistry and gel electrophoresis led to similar results, but that the colorimetric assay was inconsistent. Normal human peripheral monocytes expressed both tartrate-sensitive and -resistant AcP. In culture these cells formed polykaryons and expressed TRAcP activity that was further identified as an isoenzyme associated with bone tissue. In contrast, the U937 cells did not express TRAcP activity as measured by gel electrophoresis. Both U937 cells and monocytes possess material that interferes with interpretation of the colorimetric assay of AcP. The presence of TRAcP in monocyte-derived macrophages further supports the relationship between phagocytic cells and bone osteoclasts.
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Snipes, RG, KW Lam, RC Dodd, TK Gray, and MS Cohen. "Acid phosphatase activity in mononuclear phagocytes and the U937 cell line: monocyte-derived macrophages express tartrate-resistant acid phosphatase." Blood 67, no. 3 (March 1, 1986): 729–34. http://dx.doi.org/10.1182/blood.v67.3.729.bloodjournal673729.
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Tartrate-resistant acid phosphatase (TRAcP) is used as a marker for osteoclasts, which are believed to be derived from phagocytic cells or phagocyte stem cell precursors. To further investigate the relationship between monocytic phagocytes and osteoclasts, acid phosphatase (AcP) activity was measured by three different techniques in human peripheral blood monocytes, monocyte-derived macrophages, and the U937 cell line. We found that cytochemistry and gel electrophoresis led to similar results, but that the colorimetric assay was inconsistent. Normal human peripheral monocytes expressed both tartrate-sensitive and -resistant AcP. In culture these cells formed polykaryons and expressed TRAcP activity that was further identified as an isoenzyme associated with bone tissue. In contrast, the U937 cells did not express TRAcP activity as measured by gel electrophoresis. Both U937 cells and monocytes possess material that interferes with interpretation of the colorimetric assay of AcP. The presence of TRAcP in monocyte-derived macrophages further supports the relationship between phagocytic cells and bone osteoclasts.
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Marteijn, Jurgen A. F., Laurens T. van der Meer, Liesbeth Van Emst, Theo de Witte, Joop H. Jansen, and Bert A. van der Reijden. "Diminished proteasomal degradation results in accumulation of Gfi1 protein in monocytes." Blood 109, no. 1 (August 3, 2006): 100–108. http://dx.doi.org/10.1182/blood-2006-02-003590.
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Abstract Gfi1 is a transcriptional repressor essential during myeloid differentiation. Gfi1−/− mice exhibit a block in myeloid differentiation resulting in the accumulation of an immature myelo-monocytic cell population and the complete absence of mature neutrophils. Even though mRNA levels of Gfi1 appear to be very low in monocytes, Gfi1 might play a role in the monocytic lineage as Gfi1−/− mice exhibit diminished monocyte-derived dendritic cells and disturbed cytokine production by macrophages in response to LPS. We show here that Gfi1 protein levels are mainly regulated by the ubiquitin-proteasome system. Upon forced monocytic differentiation of U937 cells, Gfi1 mRNA levels dropped but protein levels increased due to diminished proteasomal turnover. Similarly, Gfi1 mRNA levels are low in primary monocytes whereas the protein is clearly detectable. Conversely, Gfi1 mRNA levels are high in granulocytes but the protein is swiftly degraded by the proteasome in these cells. Chromatin immunoprecipitation experiments showed that Gfi1 binds to the promoter of several granulocyte-specific genes in primary monocytes, including C/EBPα, neutrophil elastase, and Gfi1 itself. The binding of the repressor Gfi1 to these promoters correlated with low expression of these genes in monocytes compared with granulocytes. Our data fit a model in which Gfi1 protein levels are induced in primary monocytes, due to diminished proteasomal degradation, to repress genes that play a role in granulocytic differentiation.
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Wang, J. M., D. W. McVicar, J. J. Oppenheim, and D. J. Kelvin. "Identification of RANTES receptors on human monocytic cells: competition for binding and desensitization by homologous chemotactic cytokines." Journal of Experimental Medicine 177, no. 3 (March 1, 1993): 699–705. http://dx.doi.org/10.1084/jem.177.3.699.
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RANTES (regulated on activation, normal T expressed and secreted) is a member of the chemotactic cytokine (chemokine) beta subfamily. High affinity receptors for RANTES have been identified on a human monocytic leukemia cell line THP-1, which responded to RANTES in chemotaxis and calcium mobilization assays. Steady-state binding data analyses revealed approximately 700 binding sites/cell on THP-1 cells with a Kd value of 400 pM, comparable to that expressed on human peripheral blood monocytes. The RANTES binding to monocytic cells was competed for by monocyte chemotactic and activating factor (MCAF) and macrophage inflammatory protein 1 (MIP-1) alpha, two other chemokine beta cytokines. Although MCAF and MIP-1 alpha competed for RANTES binding to monocytes with apparent lower affinity (with estimated Kd of 6 and 1.6, nM respectively) both of these cytokines effectively desensitized the calcium mobilization induced by RANTES. The chemotactic response of THP-1 cells to RANTES was also markedly inhibited by preincubation with MCAF or MIP-1 alpha. In contrast, RANTES did not desensitize the THP-1 calcium mobilization and chemotaxis in response to MCAF or MIP-1 alpha. These results, together with our previous observations that RANTES did not compete for MCAF or MIP-1 alpha binding on monocytic cells, indicate the expression of promiscuous receptors on monocytes that recognize one or more cytokines within the chemokine beta family.
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Bosco, Maria Carla, Sandra Rottschafer, Lynn S. Taylor, John R. Ortaldo, Dan L. Longo, and Igor Espinoza-Delgado. "The Antineoplastic Agent Bryostatin-1 Induces Proinflammatory Cytokine Production in Human Monocytes: Synergy With Interleukin-2 and Modulation of Interleukin-2Rγ Chain Expression." Blood 89, no. 9 (May 1, 1997): 3402–11. http://dx.doi.org/10.1182/blood.v89.9.3402.
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Abstract The antineoplastic agent bryostatin-1 (bryo-1) possesses powerful immunomodulatory properties and can function as a biological response modifier in vivo. However, there is currently little information regarding the effects of bryo-1 on cells of the monocytic lineage. In this study, we demonstrate that bryo-1 can potently induce the production of proinflammatory cytokines from human peripheral blood monocytes. Stimulation of monocytes with subnanomolar concentrations of bryo-1 significantly upregulated the constitutive levels of interleukin-8 (IL-8) mRNA and induced the expression of IL-1β, tumor necrosis factor-α (TNF-α), and IL-6 mRNA in a time and dose-dependent manner. Accordingly, secretion of all four proinflammatory cytokines was induced after monocyte exposure to bryo-1. Furthermore, we showed that bryo-1 selectively synergized with IL-2 in triggering monocyte activation, and this effect seemed to be dependent, at least in part, on the ability of bryo-1 to upregulate IL-2Rγ chain expression. Finally, we demonstrated that the responses of monocytes to bryo-1 could be blocked by the protein kinase C (PKC) inhibitors staurosporine and UCN-01, indicating a role for PKC in monocyte activation by bryo-1. These results show for the first time that bryo-1 is a powerful activator of human monocytes and suggest that stimulation of monokine secretion by bryo-1 may represent at least one of the mechanisms responsible for the in vivo antitumor activity of this drug.
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Lo, Siu K., Douglas T. Golenbock, Philip M. Sass, Azmat Maskati, Hong Xu, and Roy L. Silverstein. "Engagement of the Lewis X Antigen (CD15) Results in Monocyte Activation." Blood 89, no. 1 (January 1, 1997): 307–14. http://dx.doi.org/10.1182/blood.v89.1.307.
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Abstract We previously reported that monocyte adhesion to tumor necrosis factor-α (TNF-α)–treated endothelial cells increased expression of tissue factor and CD36 on monocytes. Using immunological cross-linking to mimic receptor engagement by natural ligands, we now show that CD15 (Lewis X), a monocyte counter-receptor for endothelial selectins may participate in this response. We used cytokine production as a readout for monocyte activation and found that CD15 cross-linking induced TNF-α release from peripheral blood monocytes and cells from the monocytic cell line MM6. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) showed an increase in steady-state TNF-α mRNA after 3 to 4 hours of cross-linking. CD15 cross-linking also concomitantly increased interleukin-1β (IL-1β) mRNA, while no apparent change was observed in the levels of β-actin mRNA, indicating specificity. To examine transcriptional regulation of cytokine genes by CD15 engagement, a CAT plasmid reporter construct containing IL-1β promoter/enhancer sequences was introduced into MM6. Subsequent cross-linking of CD15 increased CAT activity. CD15 engagement by monoclonal antibody also attenuated IL-1β transcript degradation, demonstrating that signaling via CD15 also had posttranscriptional effects. Nuclear extracts of anti-CD15 cross-linked cells demonstrated enhanced levels of the transcriptional factor activator protein-1, minimally changed nuclear factor-κB, and did not affect SV40 promoter specific protein-1. We conclude that engagement of CD15 on monocytes results in monocyte activation. In addition to its well-recognized adhesive role, CD15 may function as an important signaling molecule capable of initiating proinflammatory events in monocytes that come into contact with activated endothelium.
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Lo, Siu K., Douglas T. Golenbock, Philip M. Sass, Azmat Maskati, Hong Xu, and Roy L. Silverstein. "Engagement of the Lewis X Antigen (CD15) Results in Monocyte Activation." Blood 89, no. 1 (January 1, 1997): 307–14. http://dx.doi.org/10.1182/blood.v89.1.307.307_307_314.
Full textAbstract:
We previously reported that monocyte adhesion to tumor necrosis factor-α (TNF-α)–treated endothelial cells increased expression of tissue factor and CD36 on monocytes. Using immunological cross-linking to mimic receptor engagement by natural ligands, we now show that CD15 (Lewis X), a monocyte counter-receptor for endothelial selectins may participate in this response. We used cytokine production as a readout for monocyte activation and found that CD15 cross-linking induced TNF-α release from peripheral blood monocytes and cells from the monocytic cell line MM6. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) showed an increase in steady-state TNF-α mRNA after 3 to 4 hours of cross-linking. CD15 cross-linking also concomitantly increased interleukin-1β (IL-1β) mRNA, while no apparent change was observed in the levels of β-actin mRNA, indicating specificity. To examine transcriptional regulation of cytokine genes by CD15 engagement, a CAT plasmid reporter construct containing IL-1β promoter/enhancer sequences was introduced into MM6. Subsequent cross-linking of CD15 increased CAT activity. CD15 engagement by monoclonal antibody also attenuated IL-1β transcript degradation, demonstrating that signaling via CD15 also had posttranscriptional effects. Nuclear extracts of anti-CD15 cross-linked cells demonstrated enhanced levels of the transcriptional factor activator protein-1, minimally changed nuclear factor-κB, and did not affect SV40 promoter specific protein-1. We conclude that engagement of CD15 on monocytes results in monocyte activation. In addition to its well-recognized adhesive role, CD15 may function as an important signaling molecule capable of initiating proinflammatory events in monocytes that come into contact with activated endothelium.
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Glorieux, G., C. H. Hsu, R. de Smet, A. Dhondt, J. van Kaer, P. Vogeleere, N. Lameire, and R. Vanholder. "Inhibition of calcitriol-induced monocyte CD14 expression by uremic toxins: role of purines." Journal of the American Society of Nephrology 9, no. 10 (October 1998): 1826–31. http://dx.doi.org/10.1681/asn.v9101826.
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End-stage renal disease is associated with a defect in immunologic functions. Previous studies have demonstrated that uremic ultrafiltrate (UUF) contains factors that suppress calcitriol synthesis and its biological actions. In the present study, the effect of UUF on basal and calcitriol-induced membrane bound CD14 expression of monocytes activated by phorbol 12-myristate 13-acetate was evaluated. CD14 acts as a receptor for the complexes of lipopolysaccharide and lipopolysaccharide-binding protein. Monocytes isolated from normal donors were used for the assay of monocyte CD14 expression. A calcitriol induced rise in monocyte CD14 expression (1966+/-423 to 2421+/-436 fluorescence intensity) was found. However, UUF not only suppressed basal CD14 expression of monocytes (from 1966+/-423 to 1240+/-203, P < 0.05) but also significantly blunted calcitriol-induced CD14 expression (from 2421+/-436 to 1744+/-229, P < 0.05). HPLC fractionated UUF collected from 8 to 16 min (fraction 1, F1) and from 25 to 40 min (fraction 3, F3) also significantly suppressed the expression of CD14. Because purine derivatives coeluted within F1, their effect on monocyte CD14 expression was also tested. Uric acid, xanthine, and hypoxanthine was found to suppress basal as well as calcitriol-induced CD14 expression of monocytes in a dose-dependent manner. In conclusion, UUF contains factors that impair calcitriol activated function of monocytes.
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Mya, Hae Tha, Maria Diez Campelo, Sandra Valle Herrero, Agustin Díaz-Alvarez, Domingo Bustos, Luis M. Vaquero, José J. Pérez, et al. "PD-1 and PD-L1 Are Overexpressed in the "Intermediate CD14+CD16+" and "Non Classical CD14lowCD16+" but Not in the "Classical CD14+CD16-" Monocytes in the Peripheral Blood of Chronic Myelomonocytic Leukemia." Blood 126, no. 23 (December 3, 2015): 1694. http://dx.doi.org/10.1182/blood.v126.23.1694.1694.
Full textAbstract:
Abstract Chronic myelomonocytic Leukemia (CMML) is a heterogeneous clonal disorder highly resistant to the few therapies that are available nowadays. There is increasing evidence to suggest that Programmed Death-1 (PD-1), and its major ligand Programmed Death Ligand-1 (PD-L1), are involved in immune suppression and disease progression, are highly expressed in many hematological malignancies, and can be involved in MDS pathogenesis and resistance mechanisms to hypomethylating agents. However, the expression of PD-1 and PD-L1 is not widely explored in CMML. Different types of monocytes based on CD14 and CD16 expression show different genetic profiles and functions, having different distribution in several conditions, including malignancy. In our study, we studied the expression of PD-1 and PD-L1 in the peripheral blood (PB) monocytic compartment of patients with CMML using flow cytometry , to better understand their potential role in the pathogenesis of the disease, and as a basis for the evaluation of this pathway for the development of future immunotherapy strategies. Peripheral blood samples from 16 CMML, and age matched normal (n=10) and reactive (n=9) monocytosis (>1 x109 /L) were studied. Two hundred µl of each PB sample were stained with an 8-color panel of monoclonal antibodies (CD16-FITC, CD64-PE, PD1-PCP5.5, PDL1-PC7, CD300-APC, CD14-APCH7, HLADR-V450 and CD45-OC515). A minimum of 1x 106 events were acquired by FACSCanto II (BD Biosciences, San Jose, USA) and the data was analyzed with the Infinicyt software (Cytognos SL, Spain). Monocytic population was selected first on the automated population separator plot and confirmed by the expression of CD64 and HLADR expression. Lymphocytes were used as the internal control. Three types of monocytes were defined based on the CD14 and CD16 expression, as previously described. As expected, CMML type 1 patients had higher absolute monocyte counts in PB than reactive and normal cases (p=0.001), and higher percentage of monocytic cells by flow (0.001). The distribution (median) of the monocytic subpopulations based on CD14 and CD16 expression among the monocytic compartment in PB of CMML, reactive and normal cases, respectively, was as follows: "classical"(CD14+CD16-) were of 98%, 90% and 85% (p<0.000); "intermediate" (CD14+CD16+) 1.4%, 3.7% and 2.6% (p=0.01); and "non-classical" (CD14lowCD16+) monocytes 1%, 5% and 12% (p<0.001). The expression of PD-1 in the major population ("classical" monocyte) was similar among CMML (Median MFI 370), reactive (Median MFI 403), and normal cases (Median MFI 265). However, in the "intermediate CD14+CD16+" and in the "non-classical CD14lowCD16+" monocytes, PD-1 was overexpressed in CMML and reactive cases, compared to normal controls. Reactive cases had even a higher overexpression of PD1 in both "intermediate" and "non-classical" monocytes compared to CMML (Median MFI of 312, 529, and 398 for "intermediate" and Median MFI of 185, 465, and 271 for "non- classical" in normal, reactive and CMML cases, respectively-p=0.01, and p<0.01). For PDL1, we did not find differences in their expression in "classical" nor "intermediate" monocytes among CMML, reactive and normal cases (Median MFI in "classical" monocytes of 2415 vs 2086 vs 2003 for CMML, reactive and normal cases -p>0.05-; and Median MFI in "intermediate" monocytes of 3803 vs 2737 vs 3200 for CMML, reactive and normal cases -p>0.05-). However, in the "non-classical" monocytic population, PD-L1 was clearly overexpressed in CMML (Median MFI of 1782) compared to normal controls (Median MFI of 699), and this was also significantly higher than in reactive cases (Median MFI of 1040) (p=0.002). We found that PD-1 and PD-L1 were overexpressed in CMML, but not in the main "classical" monocyte population of the PB, but in the less represented "intermediate" and "non classical" monocytic compartment. Interestingly, the CD16+ monocytes (intermediate and non-classical) were proposed to have a more important role in inflammation and immunomodulation. Therefore, these populations could have an important function in the pathogenesis of the CMML, and the overexpression of PD-1 and PD-L1 could be investigated as a target for immunotherapy in the development of new therapeutical strategies to improve the adverse prognosis of the CMML. Disclosures Diez Campelo: Novartis: Research Funding, Speakers Bureau; Janssen: Research Funding; Celgene: Research Funding, Speakers Bureau. Puig:The Binding Site: Consultancy; Janssen: Consultancy.
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Malm, Christer, Rodica Lenkei, and Bertil Sjödin. "Effects of eccentric exercise on the immune system in men." Journal of Applied Physiology 86, no. 2 (February 1, 1999): 461–68. http://dx.doi.org/10.1152/jappl.1999.86.2.461.
Full textAbstract:
The effects of eccentric exercise on changes in numbers of circulating leukocytes, cell activation, cell adhesion, and cellular memory function were investigated in 12 men, aged 22–35 yr. The immunologic effects of postexercise epidermal treatment with monochromatic, infrared light were also evaluated. Blood was drawn before and 6, 24, and 48 h after exercise for phenotyping and analysis of creatine kinase activity. There was an increase in leukocyte, monocyte, and neutrophil number, no change in the number of basophils, eosinophils, B cells, and T cells, and a decrease in natural killer cell number postexercise. Some markers of lymphocyte and monocyte activation remained unchanged or decreased, whereas the expression of adhesion molecules 62L and 11b increased on monocytes. It is concluded that eccentric exercise induced decreased activation, and increased cell adhesion capacity, of monocytes. Altered trafficking of cells between lymphoid tissue and blood, selective apoptosis, or attachment/detachment from the endothelial wall can explain the observed phenotypic changes. Treatment with monochromatic, infrared light did not significantly affect any of the investigated variables. Correlations between immunologic and physiological parameters indicate a role of the immune system in adaptation to physical exercise.
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Sariban, E., T. Mitchell, A. Rambaldi, and DW Kufe. "c-sis but not c-fos gene expression is lineage specific in human myeloid cells." Blood 71, no. 2 (February 1, 1988): 488–93. http://dx.doi.org/10.1182/blood.v71.2.488.488.
Full textAbstract:
Abstract Expression of both the c-fos and c-sis protooncogenes during myeloid differentiation has been detected in cells of the monocytic lineage. Since an increase in c-fos transcripts was not detected during dimethylsulfoxide induced HL-60 granulocytic differentiation, it was suggested that within the myeloid series c-fos gene expression might be lineage specific. In the present study, we have determined whether expression of the c-fos and c-sis genes is indeed specific for the monocytic pathway or rather common to both the granulocyte and monocyte pathways. C-fos and c-sis gene expression was analyzed in freshly isolated human granulocytes and monocytes, in human HL-60 promyelocytic leukemia cells induced to differentiate along the granulocytic or monocytic pathway, in myeloblasts from five patients with the M1 or M2 subtype of acute myeloblastic leukemia (AML) and in blasts from six patients with M4 myelomonocytic leukemia. The level of c-fos mRNA was fifteen times higher in granulocytes as compared with monocytes. An increase in c-fos expression was also found in HL-60 cells differentiated along the granulocytic pathway after exposure to hypoxanthine, hexamethylene bisacetamide, and the combination of retinoic acid and dibutyryl adenosine 3′5′ cyclic monophosphate. Three of 5 M1 and M2 leukemic myeloblast preparations depleted of lymphoid and monocytic cells and all six M4 leukemic cells expressed c-fos transcripts. In contrast, c-sis gene transcripts were detectable in monocytes and during drug induced monocytic differentiation of the HL- 60 cells but not in granulocytes during granulocytic differentiation of the HL-60 cells or in AML samples. Thus, in the myeloid series, c-sis gene expression is lineage specific while expression of the c-fos gene is found in both lineages and may be related to metabolic pathways common to both granulocytes and monocytes.
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Sariban, E., T. Mitchell, A. Rambaldi, and DW Kufe. "c-sis but not c-fos gene expression is lineage specific in human myeloid cells." Blood 71, no. 2 (February 1, 1988): 488–93. http://dx.doi.org/10.1182/blood.v71.2.488.bloodjournal712488.
Full textAbstract:
Expression of both the c-fos and c-sis protooncogenes during myeloid differentiation has been detected in cells of the monocytic lineage. Since an increase in c-fos transcripts was not detected during dimethylsulfoxide induced HL-60 granulocytic differentiation, it was suggested that within the myeloid series c-fos gene expression might be lineage specific. In the present study, we have determined whether expression of the c-fos and c-sis genes is indeed specific for the monocytic pathway or rather common to both the granulocyte and monocyte pathways. C-fos and c-sis gene expression was analyzed in freshly isolated human granulocytes and monocytes, in human HL-60 promyelocytic leukemia cells induced to differentiate along the granulocytic or monocytic pathway, in myeloblasts from five patients with the M1 or M2 subtype of acute myeloblastic leukemia (AML) and in blasts from six patients with M4 myelomonocytic leukemia. The level of c-fos mRNA was fifteen times higher in granulocytes as compared with monocytes. An increase in c-fos expression was also found in HL-60 cells differentiated along the granulocytic pathway after exposure to hypoxanthine, hexamethylene bisacetamide, and the combination of retinoic acid and dibutyryl adenosine 3′5′ cyclic monophosphate. Three of 5 M1 and M2 leukemic myeloblast preparations depleted of lymphoid and monocytic cells and all six M4 leukemic cells expressed c-fos transcripts. In contrast, c-sis gene transcripts were detectable in monocytes and during drug induced monocytic differentiation of the HL- 60 cells but not in granulocytes during granulocytic differentiation of the HL-60 cells or in AML samples. Thus, in the myeloid series, c-sis gene expression is lineage specific while expression of the c-fos gene is found in both lineages and may be related to metabolic pathways common to both granulocytes and monocytes.
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Radzun, HJ, H. Kreipe, S. Bodewadt, ML Hansmann, J. Barth, and MR Parwaresch. "Ki-M8 monoclonal antibody reactive with an intracytoplasmic antigen of monocyte/macrophage lineage." Blood 69, no. 5 (May 1, 1987): 1320–27. http://dx.doi.org/10.1182/blood.v69.5.1320.1320.
Full textAbstract:
Abstract A monoclonal antibody (MoAb), Ki-M8, that reacts specifically with cells of the monocyte/macrophage system is described. On light and electron microscopic immunohistochemistry, Ki-M8 recognizes intracytoplasmatically localized antigens of mol wt 30,000 and 32,000, increasingly expressed during differentiation of monocytes into macrophages. Ki-M8 antigen is detectable on almost all known tissue macrophages and monocyte/macrophage-related cell lines after appropriate stimulation. In functional terms Ki-M8 significantly impairs the generation of oxygen radicals during an induced respiratory burst. Applied to acute nonlymphoblastic leukemias, a clear-cut differentiation of the monocytic phenotype and differentiation is possible on the basis of Ki-M8 immunoreactivity. Ki-M8 represents a reagent specific for the monocyte/macrophage system with regard to antigen distribution in normal and neoplastic cells as well as with regard to its influence on a typical monocyte/macrophage-related function.
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Radzun, HJ, H. Kreipe, S. Bodewadt, ML Hansmann, J. Barth, and MR Parwaresch. "Ki-M8 monoclonal antibody reactive with an intracytoplasmic antigen of monocyte/macrophage lineage." Blood 69, no. 5 (May 1, 1987): 1320–27. http://dx.doi.org/10.1182/blood.v69.5.1320.bloodjournal6951320.
Full textAbstract:
A monoclonal antibody (MoAb), Ki-M8, that reacts specifically with cells of the monocyte/macrophage system is described. On light and electron microscopic immunohistochemistry, Ki-M8 recognizes intracytoplasmatically localized antigens of mol wt 30,000 and 32,000, increasingly expressed during differentiation of monocytes into macrophages. Ki-M8 antigen is detectable on almost all known tissue macrophages and monocyte/macrophage-related cell lines after appropriate stimulation. In functional terms Ki-M8 significantly impairs the generation of oxygen radicals during an induced respiratory burst. Applied to acute nonlymphoblastic leukemias, a clear-cut differentiation of the monocytic phenotype and differentiation is possible on the basis of Ki-M8 immunoreactivity. Ki-M8 represents a reagent specific for the monocyte/macrophage system with regard to antigen distribution in normal and neoplastic cells as well as with regard to its influence on a typical monocyte/macrophage-related function.
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Wolk, Kerstin, Wolf-Dietrich Döcke, Volker von Baehr, Hans-Dieter Volk, and Robert Sabat. "Impaired antigen presentation by human monocytes during endotoxin tolerance." Blood 96, no. 1 (July 1, 2000): 218–23. http://dx.doi.org/10.1182/blood.v96.1.218.
Full textAbstract:
Abstract Endotoxin tolerance (ET) has been described as a temporary alteration in the lipopolysaccharide (LPS) response of monocytic cells after an initial LPS exposure with respect to the production of soluble immunomodulators. Apart from the LPS response, monocytic cells play an important role in initiation of the specific immune response as antigen-presenting cells. This study investigated the capacity of human blood monocytes to induce T-cell stimulation in ET. First, the expression of monocyte surface molecules, important for T-cell interaction, was analyzed by flow cytometry. In vitro priming of peripheral blood mononuclear cells with LPS clearly down-regulates major histocompatibility complex class II molecules and the costimulatory molecule CD86. Both changes were dependent on the endogenous interleukin (IL)-10 and less so on the transforming growth factor-β. In contrast, other accessory molecules on monocytes were only marginally down-regulated (CD58), were not significantly changed during ET (CD40), or even remained up-regulated after initial LPS priming (CD54, CD80). Second, an impact of these phenotypic alterations on the accessory function of monocytes was observed. This was manifested as diminished T-cell proliferation and interferon (IFN)-γ release in response to the presence of different recall antigens. Neutralizing IL-10 during LPS priming prevented the diminished T-cell IFN-γ production but had little effect on T-cell proliferation. These data confirm that ET is an appropriate model of the monocyte functional state in immunoparalysis, which is frequently observed in patients after septic shock, trauma, or major surgery.
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Wolk, Kerstin, Wolf-Dietrich Döcke, Volker von Baehr, Hans-Dieter Volk, and Robert Sabat. "Impaired antigen presentation by human monocytes during endotoxin tolerance." Blood 96, no. 1 (July 1, 2000): 218–23. http://dx.doi.org/10.1182/blood.v96.1.218.013k04_218_223.
Full textAbstract:
Endotoxin tolerance (ET) has been described as a temporary alteration in the lipopolysaccharide (LPS) response of monocytic cells after an initial LPS exposure with respect to the production of soluble immunomodulators. Apart from the LPS response, monocytic cells play an important role in initiation of the specific immune response as antigen-presenting cells. This study investigated the capacity of human blood monocytes to induce T-cell stimulation in ET. First, the expression of monocyte surface molecules, important for T-cell interaction, was analyzed by flow cytometry. In vitro priming of peripheral blood mononuclear cells with LPS clearly down-regulates major histocompatibility complex class II molecules and the costimulatory molecule CD86. Both changes were dependent on the endogenous interleukin (IL)-10 and less so on the transforming growth factor-β. In contrast, other accessory molecules on monocytes were only marginally down-regulated (CD58), were not significantly changed during ET (CD40), or even remained up-regulated after initial LPS priming (CD54, CD80). Second, an impact of these phenotypic alterations on the accessory function of monocytes was observed. This was manifested as diminished T-cell proliferation and interferon (IFN)-γ release in response to the presence of different recall antigens. Neutralizing IL-10 during LPS priming prevented the diminished T-cell IFN-γ production but had little effect on T-cell proliferation. These data confirm that ET is an appropriate model of the monocyte functional state in immunoparalysis, which is frequently observed in patients after septic shock, trauma, or major surgery.
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Kaneki, M., S. Inoue, T. Hosoi, Y. Mizuno, Y. Akedo, A. Ikegami, T. Nakamura, M. Shiraki, H. Ito, and S. Suzu. "Effects of 1 alpha,25-dihydroxyvitamin D3 on macrophage colony- stimulating factor production and proliferation of human monocytic cells." Blood 83, no. 8 (April 15, 1994): 2285–93. http://dx.doi.org/10.1182/blood.v83.8.2285.2285.
Full textAbstract:
Abstract 1 alpha-25-Dihydroxyvitamin D3 [1 alpha,25(OH)2D3] stimulates the proliferation of human monocytes in vitro. In the present study, we investigated a possible role of macrophage colony-stimulating factor (M- CSF) in 1 alpha,25(OH)2D3-induced proliferation of human circulating monocytes and the effects of 1 alpha,25(OH)2D3 on M-CSF production by human monocytic cells. Both 1 alpha,25(OH)2D3 and recombinant human M- CSF increased 2.5-fold the nucleus number of human circulating monocytes on day 6 of the culture. These effects were inhibited by antihuman M-CSF antibody as well as by anti-c-fms antibody, although these antibodies themselves did not affect the nucleus number when added to control culture. These results indicated that M-CSF is required for 1 alpha,25(OH)2D3-stimulated monocyte proliferation. In addition, 1 alpha,25(OH)2D3 stimulated M-CSF secretion from human circulating monocytes. Secretion and mRNA expression of M-CSF by 12–0- tetradecanoylphorbol-13-acetate (TPA)-treated THP-1 cells (human monocytic leukemia cell line) and TPA-treated HL-60 cells (human promyelocytic leukemia cell line) were also increased by 1 alpha,25(OH)2D3. M-CSF secretion from TPA-treated THP-1 cells was increased by 1 alpha,25(OH)2D3 in a dose-dependent and metabolite- specific manner. The present study demonstrates that 1 alpha,25(OH)2D3 is a potent stimulator for M-CSF production by human monocytic cells and that the proliferative effect of 1 alpha,25(OH)2D3 on human monocytes may be attributed, at least in part, to the stimulated secretion of M-CSF.
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Kaneki, M., S. Inoue, T. Hosoi, Y. Mizuno, Y. Akedo, A. Ikegami, T. Nakamura, M. Shiraki, H. Ito, and S. Suzu. "Effects of 1 alpha,25-dihydroxyvitamin D3 on macrophage colony- stimulating factor production and proliferation of human monocytic cells." Blood 83, no. 8 (April 15, 1994): 2285–93. http://dx.doi.org/10.1182/blood.v83.8.2285.bloodjournal8382285.
Full textAbstract:
1 alpha-25-Dihydroxyvitamin D3 [1 alpha,25(OH)2D3] stimulates the proliferation of human monocytes in vitro. In the present study, we investigated a possible role of macrophage colony-stimulating factor (M- CSF) in 1 alpha,25(OH)2D3-induced proliferation of human circulating monocytes and the effects of 1 alpha,25(OH)2D3 on M-CSF production by human monocytic cells. Both 1 alpha,25(OH)2D3 and recombinant human M- CSF increased 2.5-fold the nucleus number of human circulating monocytes on day 6 of the culture. These effects were inhibited by antihuman M-CSF antibody as well as by anti-c-fms antibody, although these antibodies themselves did not affect the nucleus number when added to control culture. These results indicated that M-CSF is required for 1 alpha,25(OH)2D3-stimulated monocyte proliferation. In addition, 1 alpha,25(OH)2D3 stimulated M-CSF secretion from human circulating monocytes. Secretion and mRNA expression of M-CSF by 12–0- tetradecanoylphorbol-13-acetate (TPA)-treated THP-1 cells (human monocytic leukemia cell line) and TPA-treated HL-60 cells (human promyelocytic leukemia cell line) were also increased by 1 alpha,25(OH)2D3. M-CSF secretion from TPA-treated THP-1 cells was increased by 1 alpha,25(OH)2D3 in a dose-dependent and metabolite- specific manner. The present study demonstrates that 1 alpha,25(OH)2D3 is a potent stimulator for M-CSF production by human monocytic cells and that the proliferative effect of 1 alpha,25(OH)2D3 on human monocytes may be attributed, at least in part, to the stimulated secretion of M-CSF.
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Bauer, J., T. M. Bauer, T. Kalb, T. Taga, G. Lengyel, T. Hirano, T. Kishimoto, G. Acs, L. Mayer, and W. Gerok. "Regulation of interleukin 6 receptor expression in human monocytes and monocyte-derived macrophages. Comparison with the expression in human hepatocytes." Journal of Experimental Medicine 170, no. 5 (November 1, 1989): 1537–49. http://dx.doi.org/10.1084/jem.170.5.1537.
Full textAbstract:
IL-6 is a cytokine with pleiotropic biological functions, including induction of the hepatic acute phase response and differentiation of activated B cells into Ig-secreting plasma cells. We found that human peripheral blood monocytes express the IL-6-R, which is undetectable on the large majority of lymphocytes of healthy individuals. Stimulation of monocytes by endotoxin or IL-1 causes a rapid downregulation of IL-6-R mRNA levels and a concomitant enhancement of IL-6 mRNA expression. IL-6 itself was found to suppress the IL-6-R at high concentrations. A gradual decrease of IL-6-R mRNA levels was observed along in vitro maturation of monocytes into macrophages. We show that downregulation of IL-6-R mRNA levels by IL-1 and IL-6 is monocyte specific, since IL-6-R expression is stimulated by both IL-1 and IL-6 in cultured human primary hepatocytes. Our data indicate that under noninflammatory conditions, monocytes may play a role in binding of trace amounts of circulating IL-6. Repression of monocytic IL-6-R and stimulation of hepatocytic IL-6-R synthesis may represent a shift of the IL-6 tissue targets under inflammatory conditions.
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Ancuta, Petronela, Ravi Rao, Ashlee Moses, Andrew Mehle, Sunil K. Shaw, F. William Luscinskas, and Dana Gabuzda. "Fractalkine Preferentially Mediates Arrest and Migration of CD16+ Monocytes." Journal of Experimental Medicine 197, no. 12 (June 16, 2003): 1701–7. http://dx.doi.org/10.1084/jem.20022156.
Full textAbstract:
CD16+ monocytes represent 5–10% of peripheral blood monocytes in normal individuals and are dramatically expanded in several pathological conditions including sepsis, human immunodeficiency virus 1 infection, and cancer. CD16+ monocytes produce high levels of proinflammatory cytokines and may represent dendritic cell precursors in vivo. The mechanisms that mediate the recruitment of CD16+ monocytes into tissues remain unknown. Here we investigate molecular mechanisms of CD16+ monocyte trafficking and show that migration of CD16+ and CD16− monocytes is mediated by distinct combinations of adhesion molecules and chemokine receptors. In contrast to CD16− monocytes, CD16+ monocytes expressed high CX3CR1 and CXCR4 but low CCR2 and CD62L levels and underwent efficient transendo-thelial migration in response to fractalkine (FKN; FKN/CX3CL1) and stromal-derived factor 1α (CXCL12) but not monocyte chemoattractant protein 1 (CCL2). CD16+ monocytes arrested on cell surface–expressed FKN under flow with higher frequency compared with CD16− monocytes. These results demonstrate that FKN preferentially mediates arrest and migration of CD16+ monocytes and suggest that recruitment of this proinflammatory monocyte subset to vessel walls via the CX3CR1-FKN pathway may contribute to vascular and tissue injury during pathological conditions.
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Maddox, J. F., and C. N. Serhan. "Lipoxin A4 and B4 are potent stimuli for human monocyte migration and adhesion: selective inactivation by dehydrogenation and reduction." Journal of Experimental Medicine 183, no. 1 (January 1, 1996): 137–46. http://dx.doi.org/10.1084/jem.183.1.137.
Full textAbstract:
Monocyte recruitment and adherence are important events in inflammatory and vascular diseases. Here, we evaluated the actions of lipoxin A4 (LXA4) and LXB4, a series of lipoxygenase products from arachidonic acid generated by cell-cell interactions, on human monocytes. LXA4 and LXB4 (10(-7) M) each increased monocyte migration in chamber chemotaxis assays and, in migration under agarose, exhibited chemotactic indices similar to those of the chemotactic peptide formyl-methionyl-leucyl-phenylalanine at 10(-10)-10(-8) M and to the chemokine macrophage inflammatory protein-1 alpha (MIP-1 alpha) at 10(-8)-10(-7) M with a rank order of potency: Monocyte chemotactic protein-1 alpha > LXA4 approximately LXB4 approximately MIP-1 alpha. Lipoxins also stimulated monocyte adherence to laminin. In addition, human monocytes rapidly transformed LXA4 and LXB4 to several metabolites. LXB4 (> 80%) was converted within 30 s to new products, in a trend similar to that of LXA4. The novel monocyte-derived LXB4 products were identified as 5-oxo-6,7-dihydro-LXB4 and 6,7-dihydro-LXB4, indicating a role for site-selective dehydrogenation and reduction. Unlike monocytes, intact polymorphonuclear leukocytes (PMN) did not metabolize LXA4 in significant quantities, and only approximately 12% of exogenous LXB4 was omega-oxidized to 20-OH-LXB4 and 20-COOH-LXB4 by PMN. To determine if lipoxin conversion altered bioactivity, we evaluated the actions of these metabolites on monocytes. Each of the novel products of LXA4 and LXB4 from monocytes, namely oxo- and dihydrolipoxins, were essentially inactive in stimulating monocyte adherence. In contrast, the omega-oxidation products of LXB4 isolated from PMN were equipotent with LXB4 for monocyte adherence. Dehydrogenation of LXA4 in monocytes appears to be carried out by a 15-hydroxyprostaglandin dehydrogenase, which is present in human monocytes as determined by reverse transcription PCR and Western blots. Together, these results provide the first evidence that LXA4 and LXB4 are both potent stimulants for migration and adherence of human monocytes. Moreover, they underscore the importance of the major route of lipoxin metabolism in leukocytes, namely, the rapid dehydrogenation and inactivation carried out by monocytes.
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Qu, Chunfeng, Emmerson W. Edwards, Frank Tacke, Véronique Angeli, Jaime Llodrá, Guzman Sanchez-Schmitz, Alexandre Garin, et al. "Role of CCR8 and Other Chemokine Pathways in the Migration of Monocyte-derived Dendritic Cells to Lymph Nodes." Journal of Experimental Medicine 200, no. 10 (November 8, 2004): 1231–41. http://dx.doi.org/10.1084/jem.20032152.
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Studying the influence of chemokine receptors (CCRs) on monocyte fate may reveal information about which subpopulations of monocytes convert to dendritic cells (DCs) and the migration pathways that they use. First, we examined whether prominent CCRs on different monocyte subsets, CCR2 or CX3CR1, mediated migration events upstream of the accumulation of monocyte-derived DCs in lymph nodes (LNs). Monocytes were labeled and traced by uptake of latex microspheres in skin. Unexpectedly, neither CCR2 nor CX3CR1 were required. However, absence of CCR2 led to an increased labeling of the minor Gr-1int monocyte population, and the number of latex+ DCs that emigrated to LNs was correspondingly increased. Characterization of Gr-1int monocytes revealed that they selectively expressed CCR7 and CCR8 mRNA in blood. CCR7 and CCR8 pathways were used by monocyte-derived DCs during mobilization from skin to LNs. The role of CCR8 in emigration from tissues also applied to human monocyte-derived cells in a model of transendothelial trafficking. Collectively, the data suggest that Gr-1int monocytes may be most disposed to become a lymphatic-migrating DCs. When these monocyte-derived DCs exit skin to emigrate to LNs, they use not only CCR7 but also CCR8, which was not previously recognized to participate in migration to LNs.
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Gross, Antoine, Annie Terraza, Safia Ouahrani-Bettache, Jean-Pierre Liautard, and Jacques Dornand. "In Vitro Brucella suis Infection Prevents the Programmed Cell Death of Human Monocytic Cells." Infection and Immunity 68, no. 1 (January 1, 2000): 342–51. http://dx.doi.org/10.1128/iai.68.1.342-351.2000.
Full textAbstract:
ABSTRACT During the complex interaction between an infectious agent and a host organism, the pathogen can interfere with the host cell's programmed death to its own benefit. Induction or prevention of host cell apoptosis appears to be a critical step for determining the infection outcome. Members of the gram-negative bacterial genusBrucella are intracellular pathogens which preferentially invade monocytic cells and develop within these cells. We investigated the effect of Brucella suis infection on apoptosis of human monocytic phagocytes. The present study provides evidence thatBrucella infection inhibited spontaneously occurring apoptosis in human monocytes. Prevention of monocyte apoptosis was not mediated by Brucella lipopolysaccharide and required bacterial survival within infected cells. Both invaded and noninvaded cells were protected, indicating that soluble mediators released during infection were involved in the phenomenon. Analysis ofBrucella-infected monocytes revealed specific overexpression of the A1 gene, a member of thebcl-2 family implicated in the survival of hematopoietic cells. Brucella infection also rendered macrophage-like cells resistant to Fas ligand- or gamma interferon-induced apoptosis, suggesting that Brucella infection protected host cells from several cytotoxic processes occurring at different steps of the immune response. The present data clearly show that Brucella suis modulated the monocyte/macrophage's apoptotic response to the advantage of the pathogen, thus preventing host cell elimination. This might represent a strategy for Brucella development in infected hosts.
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Lin, Haishan, Min Mei Huang, Cindy Leo, May Ji, Ge Wu, Aileen Zhou, Robert Halenbeck, et al. "A Novel Cytokine, FPT025, Regulates Myeloid Growth and Differentiation Via the M-CSF Receptor." Blood 108, no. 11 (November 16, 2006): 634. http://dx.doi.org/10.1182/blood.v108.11.634.634.
Full textAbstract:
Abstract To identify novel protein therapeutics we have utilized an integrated screening system in which a collection of full-length human cDNA clones, encoding virtually all secreted proteins and receptors, was assembled. Soluble secreted proteins were expressed in a high-throughput format using human cells as the expression host and tested in high-throughput cell-based assays. Through this approach, a novel cytokine, FPT025, was identified in a human monocyte proliferation assay. FPT025 has no apparent sequence homology to known cytokines or any other genes and is expressed in human spleen, skin, brain, and other tissues. The purified recombinant FPT025 protein stimulated human primary monocyte proliferation and/or survival. FPT025 protein specifically bound to human primary monocytes and activated ERK1/2 phosphorylation in primary monocytes as well as in a human monocytic cell line, THP-1. FPT025 promoted formation of the myeloid lineage colonies, CFU-M, in a human bone marrow colony formation assay and enhanced proliferation of cells with myeloid cell surface markers from human monocytes. To identify the receptor of FPT025, a collection of extracellular domains (ECD) of transmembrane proteins was screened for their ability to block FPT025 activation of monocyte proliferation. In this screen, we found that FPT025 binds to the M-CSF receptor (M-CSFR) with high affinity. Furthermore, we showed that the binding of FPT025 to M-CSFR was specific and could be competed by M-CSF. The soluble ECD of M-CSFR inhibited both the binding of FPT025 to M-CSFR and the activity of FPT025 in monocyte proliferation. Therefore, FPT025 functions as a novel ligand of the M-CSF receptor and participates in the regulation of myeloid lineage differentiation, proliferation, and survival.
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Oeth, P., and N. Mackman. "Salicylates inhibit lipopolysaccharide-induced transcriptional activation of the tissue factor gene in human monocytic cells." Blood 86, no. 11 (December 1, 1995): 4144–52. http://dx.doi.org/10.1182/blood.v86.11.4144.bloodjournal86114144.
Full textAbstract:
Binding of plasma Factor VII/VIIa to the tissue factor (TF) receptor initiates the coagulation protease cascades. TF expression by circulating monocytes is associated with thrombotic and inflammatory complications in a variety of diseases. Transcriptional activation of the human TF gene in monocytic cells exposed to bacterial lipopolysaccharide (LPS) is mediated by binding of c-Rel/p65 heterodimers to a kappa B site in the TF promoter. Here, we report that a family of anti-inflammatory agents, known as the salicylates, inhibited LPS induction of TF activity and TF gene transcription in human monocytes and monocytic THP-1 cells at clinically relevant doses. Furthermore, sodium salicylate blocked the LPS-induced proteolytic degradation of I kappa B alpha, which prevented the nuclear translocation of c-Rel/p65 heterodimers. In contrast, two other nonsteroidal anti-inflammatory drugs, ibuprofen and indomethacin, did not inhibit LPS induction of the TF gene. These results indicated that salicylates inhibited LPS induction of TF gene transcription in monocytic cells by preventing nuclear translocation of c-Rel/p65 heterodimers. The clinical benefits of salicylates in the treatment of several diseases, including atherosclerosis and rheumatoid arthritis, may be related to their ability to reduce monocyte gene expression.
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Chirinos, Julio A., Wenche Jy, Freddy Del Carpio, Roque Arteaga, Heresi A. Gustavo, Martin Valvidia, Lawrence L. Horstman, Joaquin J. Jimenez, and Yeon S. Ahn. "Correlation between Entothelial Microparticle Binding to Monocytes and Monocyte Nitric Oxide Production in Prothrombotic and Inflammatory Disorders." Blood 106, no. 11 (November 16, 2005): 3860. http://dx.doi.org/10.1182/blood.v106.11.3860.3860.
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Abstract Introduction: Endothelial microparticle binding to monocytes has been shown to induce monocyte activation in vitro. In this study, we examined the correlations between EMP binding to monocytes and monocyte levels of nitric oxide (NO), as a marker of monocyte activation in different clinical conditions. Methods: We studied 186 subjects with acute venous thromboembolism (n=25), atrial fibrillation (n=48), metabolic syndrome (n=37), congestive heart failure (n=44), and normal controls (n=32). Using flow cytometry, we measured monocyte levels of NO by flow cytometry after loading monocytes with the membrane permeable NO-selective fluorescent indicator DAF-DA. Two different populations of EMP-monocyte conjugates were also measured. EMP62E+-monocyte and EMP54+-monocyte conjugates were measured based on the detection of E-selectin (CD62E) or CD54, respectively, coexpressed with CD45 in monocytes. Results: Pearson correlation coefficients between monocyte NO levels and EMP-monocyte conjugates are shown in the Table. A highly significant correlation was found between EMP62E+-monocyte conjugates and monocyte NO levels in patients with congestive heart failure (r=0.43; p=0.003). In contrast, EMP54+-monocyte conjugates strongly correlated with monocyte NO in patients with venous thromboembolism (r=0.58; p=0.009) and metabolic syndrome (r=0.49; p=0.002). No correlation was found between these conjugates and monocyte NO levels in atrial fibrillation or normal controls. Conclusions: The binding of different species of EMP to monocytes correlates with monocyte NO levels in clinical states such as congestive heart failure, metabolic syndrome, and venous thromboembolism. However, this correlation was not found in atrial fibrillation or normal controls. Our findings support the concept that the binding of different species of EMP exert different biological effects and/or reflect different biologic processes in specific disease states. Further research is needed to determine whether the binding of EMP species to monocytes regulates nitric oxide production by monocytes and whether monocytes themselves regulate the binding of different species of EMP in different disease states. Correlation between Monocyte NO levels and EMP-Monocyte Conjugates in different conditions. EMP54+-Monocyte Conjugates EMP62E+-Monocyte Conjugates Pearson r p value Pearson r p value Metabolic Syndrome 0.49 0.002 0.13 0.54 Venous Thromboembolism 0.51 0.009 0.12 0.57 Congestive Heart Failure 0.22 0.14 0.43 0.003 Atrial Fibrillation 0.22 0.14 0.17 0.24 Normal Controls 0.03 0.85 0.27 0.13
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Schober, Joseph M., Ningyu Chen, Tatiana M. Grzeszkiewicz, Igor Jovanovic, Eugene E. Emeson, Tatiana P. Ugarova, Richard D. Ye, Lester F. Lau, and Stephen C. T. Lam. "Identification of integrin αMβ2 as an adhesion receptor on peripheral blood monocytes for Cyr61 (CCN1) and connective tissue growth factor (CCN2): immediate-early gene products expressed in atherosclerotic lesions." Blood 99, no. 12 (June 15, 2002): 4457–65. http://dx.doi.org/10.1182/blood.v99.12.4457.
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Cysteine-rich 61 (Cyr61, CCN1) and connective tissue growth factor (CTGF, CCN2) are growth factor–inducible immediate-early gene products found in blood vessel walls and healing cutaneous wounds. We previously reported that the adhesion of endothelial cells, platelets, and fibroblasts to these extracellular matrix–associated proteins is mediated through integrin receptors. In this study, we demonstrated that both Cyr61 and CTGF are expressed in advanced atherosclerotic lesions of apolipoprotein E–deficient mice. Because monocyte adhesion and transmigration are important for atherosclerosis, wound healing, and inflammation, we examined the interaction of THP-1 monocytic cells and isolated peripheral blood monocytes with Cyr61 and CTGF. THP-1 cells and monocytes adhered to Cyr61- or CTGF-coated wells in an activation-dependent manner and this process was mediated primarily through integrin αMβ2. Additionally, expression of αMβ2 on human embryonic kidney 293 cells resulted in enhanced cell adhesion to Cyr61. Consistent with these data, a GST-fusion protein containing the I domain of the integrin αM subunit bound specifically to immobilized Cyr61 or CTGF. We have also investigated the requirement of cell surface heparan sulfate proteoglycans (HSPGs) as coreceptors for monocyte adhesion to Cyr61. Pretreatment of monocytes with heparin or heparinase I resulted in partial inhibition of cell adhesion to Cyr61. However, monocytes, but not fibroblasts, were capable of adhering to a Cyr61 mutant deficient in heparin binding activity. Collectively, these results show that activated monocytes adhere to Cyr61 and CTGF through integrin αMβ2 and cell surface HSPGs. However, unlike fibroblast adhesion to Cyr61, cell surface HSPGs are not absolutely required for this adhesion process.
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Pavlov, O. V., S. V. Chepanov, A. V. Selutin, M. S. Zainulina, D. R. Eremeeva, and S. A. Selkov. "Flow cytofluorimetric detection and immunophenotyping of platelet-monocyte complexes in peripheral blood." Medical Immunology (Russia) 23, no. 2 (May 3, 2021): 401–10. http://dx.doi.org/10.15789/1563-0625-fcd-2124.
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Activated platelets aggregate with monocytes by binding membrane bound molecules. Platelet-monocyte interaction is considered to underlie pathophysiological mechanisms bridging thrombosis and inflammation. Detection and analysis of platelet-monocyte complexes (PMC) provide means for revealing their physiological and pathogenetic roles and are instrumental in the diagnostics of various pathological conditions including obstetric complications. The aim of the study was to develop the method of quantitative determination of peripheral blood PMC, that preserve phenotypic features of platelets and monocytes, and to reveal their changes by ex vivo analysis. The suggested procedure includes immediate fixation of blood sample, immunocytochemical staining with fluorochrome-conjugated specific antibodies against markers of activation and differentiation followed by lysis of erythrocytes, and flow cytometric analysis. Fourteen samples of peripheral blood from patients with history of pregnancy complication were obtained in first trimester of ongoing pregnancy and analyzed. It was demonstrated that quantitative and qualitative in vivo characteristics of PMC remained unchanged in fixed samples, whereas the number of PMC and expression levels of the markers of platelet and monocyte activation dramatically increased in the unfixed blood. The set of monoclonal antibodies and gating strategies, used in this study, ensure phenotyping and evaluation of percentage/absolute count of PMC in the total monocyte population (CD45+CD14+) and in the subpopulations of classical (CD14+CD16-), intermediate (CD14+CD16+), and non-classical (CD14lowCD16+) monocytes. This approach provides insight into the participation of different monocyte subsets in the formation of PMC and their roles in physiological and pathophysiological processes. In some samples, elevated PMC proportion was observed, accompanied by significant increase in the expression of platelet activation marker CD62P and decrease in the expression of its monocytic ligand CD162. These changes suggested altered activation of PMC and their participation in the pathophysiological mechanisms of some pregnancy complications. Immunophenotyping of PMC affords an opportunity to characterize their proinflammatory, procoagulant and adhesive properties; these results can be used for research and diagnostics. In particular, the method is suitable for detection and phenotyping of PMC in pregnancy complications and other pathological conditions associated with the disorders of hemostasis and thrombosis.
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Chong, Shu Zhen, Maximilien Evrard, Sapna Devi, Jinmiao Chen, Jyue Yuan Lim, Peter See, Yiru Zhang, et al. "CXCR4 identifies transitional bone marrow premonocytes that replenish the mature monocyte pool for peripheral responses." Journal of Experimental Medicine 213, no. 11 (October 10, 2016): 2293–314. http://dx.doi.org/10.1084/jem.20160800.
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It is well established that Ly6Chi monocytes develop from common monocyte progenitors (cMoPs) and reside in the bone marrow (BM) until they are mobilized into the circulation. In our study, we found that BM Ly6Chi monocytes are not a homogenous population, as current data would suggest. Using computational analysis approaches to interpret multidimensional datasets, we demonstrate that BM Ly6Chi monocytes consist of two distinct subpopulations (CXCR4hi and CXCR4lo subpopulations) in both mice and humans. Transcriptome studies and in vivo assays revealed functional differences between the two subpopulations. Notably, the CXCR4hi subset proliferates and is immobilized in the BM for the replenishment of functionally mature CXCR4lo monocytes. We propose that the CXCR4hi subset represents a transitional premonocyte population, and that this sequential step of maturation from cMoPs serves to maintain a stable pool of BM monocytes. Additionally, reduced CXCR4 expression on monocytes, upon their exit into the circulation, does not reflect its diminished role in monocyte biology. Specifically, CXCR4 regulates monocyte peripheral cellular activities by governing their circadian oscillations and pulmonary margination, which contributes toward lung injury and sepsis mortality. Together, our study demonstrates the multifaceted role of CXCR4 in defining BM monocyte heterogeneity and in regulating their function in peripheral tissues.
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Mavilio, F., U. Testa, NM Sposi, M. Petrini, E. Pelosi, C. Bordignon, S. Amadori, F. Mandelli, and C. Peschle. "Selective expression of fos proto-oncogene in human acute myelomonocytic and monocytic leukemias: a molecular marker of terminal differentiation." Blood 69, no. 1 (January 1, 1987): 160–64. http://dx.doi.org/10.1182/blood.v69.1.160.160.
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Abstract Expression of human fos proto-oncogene (c-fos) was analyzed in primary cells from 50 untreated acute lymphocytic (ALL) and myeloblastic (AML) leukemias. c-fos RNA, analyzed by blot hybridization, was detected virtually only in myelomonocytic (M4) and monocytic (M5) AML. Both M4 and M5 samples show a strong positive correlation between the amount of c-fos transcripts and the percentage of leukemic cells expressing surface antigens specific for mature monocytes and macrophages. Normal mature monocytes exhibit a detectable level of c-fos RNA, which is virtually unaltered on activation to macrophage differentiation, but is always below that observed in M4 through M5 monocyticlike cells. These data provide evidence that c-fos expression is linked to terminal monocyte and macrophage differentiation in normal and leukemic hemopoiesis.
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Mavilio, F., U. Testa, NM Sposi, M. Petrini, E. Pelosi, C. Bordignon, S. Amadori, F. Mandelli, and C. Peschle. "Selective expression of fos proto-oncogene in human acute myelomonocytic and monocytic leukemias: a molecular marker of terminal differentiation." Blood 69, no. 1 (January 1, 1987): 160–64. http://dx.doi.org/10.1182/blood.v69.1.160.bloodjournal691160.
Full textAbstract:
Expression of human fos proto-oncogene (c-fos) was analyzed in primary cells from 50 untreated acute lymphocytic (ALL) and myeloblastic (AML) leukemias. c-fos RNA, analyzed by blot hybridization, was detected virtually only in myelomonocytic (M4) and monocytic (M5) AML. Both M4 and M5 samples show a strong positive correlation between the amount of c-fos transcripts and the percentage of leukemic cells expressing surface antigens specific for mature monocytes and macrophages. Normal mature monocytes exhibit a detectable level of c-fos RNA, which is virtually unaltered on activation to macrophage differentiation, but is always below that observed in M4 through M5 monocyticlike cells. These data provide evidence that c-fos expression is linked to terminal monocyte and macrophage differentiation in normal and leukemic hemopoiesis.
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Weisheit, Christina K., Alexandra Klüners, Lennart Wild, Alexandra Casalter, Stefanie Heilmann-Heimbach, Sugirthan Sivalingam, Jan L. Kleiner, et al. "Sustained Immunoparalysis in Endotoxin-Tolerized Monocytic Cells." Mediators of Inflammation 2020 (June 13, 2020): 1–10. http://dx.doi.org/10.1155/2020/8294342.
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Sepsis is associated with a strong inflammatory reaction triggering a complex and prolonged immune response. Septic patients have been shown to develop sustained immunosuppression due to a reduced responsiveness of leukocytes to pathogens. Changes in cellular metabolism of leukocytes have been linked to this phenomenon and contribute to the ongoing immunological derangement. However, the underlying mechanisms of these phenomena are incompletely understood. In cell culture models, we mimicked LPS tolerance conditions to provide evidence that epigenetic modifications account for monocyte metabolic changes which cause immune paralysis in restimulated septic monocytes. In detail, we observed differential methylation of CpG sites related to metabolic activity in human PBMCs 18 h after septic challenge. The examination of changes in immune function and metabolic pathways was performed in LPS-tolerized monocytic THP-1 cells. Passaged THP-1 cells, inheriting initial LPS challenge, presented with dysregulation of cytokine expression and oxygen consumption for up to 7 days after the initial LPS treatment. Proinflammatory cytokine concentrations of TNFα and IL1β were significantly suppressed following a second LPS challenge (p<0.001) on day 7 after first LPS stimulation. However, the analysis of cellular metabolism did not reveal any noteworthy alterations between tolerant and nontolerant THP-1 monocytes. No quantitative differences in ATP and NADH synthesis or participating enzymes of energy metabolism occurred. Our data demonstrate that the function and epigenetic modifications of septic and tolerized monocytes can be examined in vitro with the help of our LPS model. Changes in CpG site methylation and monocyte function point to a correlation between epigenetic modification in metabolic pathways and reduced monocyte function under postseptic conditions.
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Martins, Paula da Costa, Janine M. van Gils, Anita Mol, Peter L. Hordijk, and Jaap-Jan Zwaginga. "Platelet Binding to Monocytes Induces Changes in Integrin Functionality Promoting Monocyte Adhesion and Transendothelial Migration. Do Platelets Migrate Along?." Blood 106, no. 11 (November 16, 2005): 2214. http://dx.doi.org/10.1182/blood.v106.11.2214.2214.
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Abstract Monocyte adhesion to and transmigration across the endothelium are essential steps in atherogenesis. We have shown that the adhesive interactions between monocytes and the activated endothelium are increased when platelets bind to the monocyte surface and form platelet-monocyte complexes (PMC). PMC formation is dependent on interactions between platelet-displayed P-selectin and PSGL-1 on the monocyte surface. To better understand the effect of platelet binding on the capacity of monocytes to adhere to activated endothelium the P-selectin-PSGL-1 interaction - induced changes in integrin functionality were studied. The binding of platelets to monocytes via P-selectin-PSGL-1 interactions was shown to increase expression and activity of α4 beta;1 - and αM β2 - integrins which, resulted in increased monocyte adhesion to ICAM-1, VCAM-1, fibronectin and subsequently to stimulated endothelial cells. Platelet binding also induced monocyte migration (up to a 3-fold increase), compared to monocytes without platelets on their surface. To investigate the role of platelets in this process we determined the fate of platelets (within the PMC) during monocyte transendothelial migration. After forming PMC by mixing freshly isolated and fluorescently labeled platelets and monocytes, PMC were seeded on endothelial cells cultured on top of a fibrin gel. The cells were allowed to migrate across the endothelial layer into the gel where afterwards the position of platelets and monocytes was analyzed by confocal laser scanning microscopy. We found that the platelets were retained at the endothelium, suggesting that they detach from the PMC and are left behind on the endothelial layer upon monocyte transendothelial migration. In line with this we observed that the monocytes that were in the fibrin gel, underneath the endothelial layer, did not carry any platelets. This was confirmed by PMC migration over endothelial layered transwell filters since almost only monocytes were found in the lower compartment after migration. After testing different migration barriers, platelets seem to be shed from the monocyte surface upon monocyte migration by mechanical stress rather than only endothelial interaction. Our data suggest that monocytes bound to platelets are in a higher state of activation and have an increased atherogenic capacity. Furthermore, platelets seem to mainly play a role in the monocyte recruitment to the endothelium because once the monocytes cross the endothelial layer, platelets detach from their surface. Altogether, our findings, by showing that PMC have a strong atherogenic capacity, might be helpful in finding new therapeutic ways to prevent atherosclerosis and inflammation.
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Lee, Itia, Nagavedi S. Umapathy, Aluya Oseghale, and Julia E. Brittain. "Hemolysis Induced Activation of Monocytes Is Followed By Inactivation Via Heme-Induced HO-1 Expression." Blood 124, no. 21 (December 6, 2014): 4057. http://dx.doi.org/10.1182/blood.v124.21.4057.4057.
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Abstract Introduction: Sickle cell disease (SCD) is characterized by profound erythrocyte hemolysis. Hemolytic events, both chronic and acute, lead to elevated levels of both hemoglobin and heme in patients. Both hemoglobin and heme are toxic in the vasculature, but the relative contribution of each to the overall state of health in patients is unknown. Nonetheless, hemolysis is emerging as a clear contributor to inflammation and coagulation activation. The mechanism through which hemolysis may contribute to either inflammation or coagulation activation is not well defined. The monocyte, however, is the only white blood cell in the bloodstream that is uniquely positioned to influence both coagulation activation and inflammation. Monocytes can express tissue factor (TF) on their surface and, as such, activate the extrinsic pathway of thrombin generation. Furthermore, monocytes are activated in SCD, and likely contribute to the overall inflammatory state of the disease. Thus, we reasoned that monocyte activation is a likely mechanism through which hemolysis, either via free hemoglobin or free heme, could influence both coagulation and inflammation. Another aspect of hemolysis is the persistent induction of heme-oxygenase-1 (HO-1) in the presence of elevated levels of plasma heme. We also reasoned that any interrogation of the effects of hemolysis on monocyte activation would induce the significant expression of this heme-degrading enzyme potentially mitigating long term hemolytic stress. Objectives: Determine the effects of free hemoglobin, heme, and heme-induced HO-1 expression on monocyte inflammation and pro-coagulant function. Methods: Monocyte activation was measured in response to either purified hemoglobins A or S, or heme, and was measured in THP-1 monocytes. Simultaneous analysis of 84 heme-induced inflammatory genes was conducted via qRT-PCR using the Qiagen RT Profiler PCR array. HO-1 was induced by pre-conditioning monocytes overnight in heme (5uM). Monocyte inactivation was measured using this pre-conditioning, followed by an additional treatment with 10uM heme. Monocyte TF expression was determined via flow cytometry analysis. TF specific pro-coagulant activity was determined in a one stage clotting assay. The expression of HO-1 protein in THP-1 cells was analyzed using ELISA. Results: We found, in terms of monocyte function, purified hemoglobins A or S were essentially inert. Free heme at physiological levels in patients with SCD, however, was a powerful monocyte activator. We found that, in naïve cells, heme induced profound TF expression at the cell surface, increased monocyte TF mRNA, and significantly increased the pro-coagulant potential of monocytes in a TF-dependent manner. Furthermore, we noted an acute increase in heme-modulated inflammatory gene expression in monocytes using a global gene expression analysis. Of note, there was a profound induction of inflammatory genes in the TGF-β family by heme, including BMP7. Members of the growth and differentiation family were heme-inducible as well - including GDF1,2,& 3. Expression of interleukins 3, 6, 8, 9, & 25 was all significantly increased in response to an acute heme exposure. All genes responded in a dose dependent manner to heme. There was no heme-dependent induction of TNFα suggesting a non-classical monocytic response to heme stimulation. However, sustained exposure to heme inactivated the monocyte inflammatory gene response. Furthermore, monocyte pre-conditioning in heme rendered the cells resistant to subsequent heme-induced inflammation or pro-coagulant function. This heme induced inactivation of monocyte was coincident with and linked to a robust monocyte expression of HO-1. Conclusions: We report a novel heme-induced activation of monocytes that can be directly inhibited by heme-induced HO-1 expression. Our data therefore provide evidence for the first time of a link between hemolysis and monocyte inflammatory and pro-coagulant function. These data potentially suggest that, in patients, higher levels of baseline hemolysis might be protective against the sudden, acute hemolytic event in SCD. These events often precede acute pain crisis and acute chest syndrome. Further study of monocyte activation and levels of HO-1 in patients during these events is merited. Disclosures No relevant conflicts of interest to declare.
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Altieri, D. C., and P. M. Mannucci. "Thromboxane generation by human monocytes enhances platelet function." Journal of Experimental Medicine 164, no. 5 (November 1, 1986): 1815–20. http://dx.doi.org/10.1084/jem.164.5.1815.
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Human monocytes potentiate the ADP-stimulated aggregation of autologous platelets through a fourfold increased binding of 125I-fibrinogen to the platelet surface. The enhancement of platelet function is rapid, relatively transient and is due to thromboxane (Tx) synthesized by monocytes under these conditions. Tx generation by monocytes is triggered by the interaction between fibrinogen and the specific monocyte membrane receptor. These data suggest that the monocyte enhancement of platelet function combined with the clot-promoting activity of these cells might unbalance normal hemostasis.
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Xiong, Jingbo, Kefei Kang, Liming Liu, Yuichi Yoshida, Kevin D. Cooper, and Mahmoud A. Ghannoum. "Candida albicans and Candida krusei Differentially Induce Human Blood Mononuclear Cell Interleukin-12 and Gamma Interferon Production." Infection and Immunity 68, no. 5 (May 1, 2000): 2464–69. http://dx.doi.org/10.1128/iai.68.5.2464-2469.2000.
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ABSTRACT Protection against Candida infection involves both innate and acquired immune responses, and cytokines produced by monocytes during the innate response may modify the acquired immune response by T cells. We hypothesized that Candida species which differ in pathogenicity can differentially induce production of immunoregulatory cytokines by human monocytes, which in turn modify T cells for immune responses to Candida. To test this hypothesis, we examined the effects of Candida albicans andCandida krusei on immunoregulatory cytokine production by human monocytes and gamma interferon (IFN-γ) production by peripheral blood mononuclear cells (PBMC). Purified monocytes were incubated with live or heat-killed strains of C. albicans and C. krusei at the optimal Candida/monocyte ratio of 0.5. Cytokines in the supernatants were measured by enzyme-linked immunosorbent assay. Our data demonstrated that live C. albicans and C. krusei significantly induced interleukin-10 (IL-10), monocyte chemotactic factor 1, IL-1β, and tumor necrosis factor alpha production by monocytes relative to unstimulated monocytes. In contrast, unlike C. krusei, pathogenic live strains of C. albicans induced no or only a minimal level of IL-12. The expression of IL-12 p40 mRNA levels by reverse transcription-PCR corroborated the IL-12 protein (p70) findings. In human PBMC, human blood monocytes were the major source of both IL-10 and IL-12 production in response to C. albicansand C. krusei. Upon activation of T cells in the presence of Candida-modified monocytes and antigen-presenting cells, IL-12 production by PBMC treated with Candida organisms correlated strongly with the level of IFN-γ production by T cells. These results indicate that the virulence of C. albicansmay be related to its ability to induce the monocytic type II cytokine IL-10, with a selective inhibition of IL-12 production, which may be responsible for the observed lack of T-cell IFN-γ and may restrain an effective type I immune response to Candida.
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Umapathy, Nagavedi S., Kavita Natrajan, Abdullah Kutlar, Steffen E. Meiler, and Julia E. Brittain. "Pivotal Role Of Heat Shock Proteins In Monocyte and Endothelial Cell Pathology In Sickle Cell Disease." Blood 122, no. 21 (November 15, 2013): 969. http://dx.doi.org/10.1182/blood.v122.21.969.969.
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Abstract Background It is well established that sickle cell disease (SCD) manifests global perturbations of hemostasis. Vaso-occlusion, inflammation and coagulopathy all likely contribute to the protean complications of SCD. Central to both inflammation and coagulation is the monocyte. These cells can be profoundly pro-inflammatory and can express tissue factor on their surface and thus influence both inflammation and coagulation. Monocytosis is common in SCD, as is steady state monocyte activation. Exaggerated monocytic response to stimulus may also contribute to the severity of acute events. Thus, agents that regulate monocyte function are potentially of significant relevance in SCD. To this end, we have discovered that the heat shock proteins (HSPs) are potential master regulators of these cells. We previously demonstrated that inhibition of one such HSP, HSP90, could completely ablate the profound and hyper-responsive monocytic inflammatory release upon lipopolysacchiride (LPS) challenge. Inhibition of HSP90 also blocked LPS induced NFk-B translocation to the nucleus. Thus, these results suggested a potent role for HSP90 in LPS-induced monocyte based inflammation. However, the role of HSP90 is cytokine-induced monocyte activation was speculative. The role of HSP90 in monocyte tissue factor expression, or reactive oxygen species (ROS) generation remained unknown. Objectives We sought to determine the role of HSP90 in regulating the pro-inflammatory, pro-coagulant, and ROS generating potential in monocytes. We then wanted to establish a potential role for HSP90 inhibition. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood using Ficoll density separation. Flow cytometry was employed to measure the LPS- or cytokine-induced monocyte tissue factor expression and ROS generation. Monocyte ROS generation was detected using L012 based chemiluminescence or visualized in individual cells using flow cytometry with CELLROX. Inflammatory cytokines and tissue factor gene expression was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). NFkB translocation to the nucleus was detected via cell fractionation followed by western blotting or indirect immunofluorescence. PBMCs or THP-1 cells were pre-treated with the HSP90 inhibitors 17-DMAG or AUY922 prior to assay. Monocyte- induced endothelial cell permeability was measured using endothelial cell-substrate impedance sensing (ECIS). Unless otherwise stated p<0.05. Results At baseline, PBMCs from patients with SCD demonstrated elevated monocyte ROS generation and tissue factor expression than those from healthy controls. Inhibition of significantly reduced these measures of steady state monocyte activation. HSP90 inhibition also inhibited both LPS and cytokine induced tissue mRNA accumulation and subsequent cell surface expression of tissue factor in monocytes. Cytokine- induced ROS generation was significantly interrupted in monocytes upon inhibition of HSP90. A panel of monocyte pro-inflammatory genes could be inhibited with AUY922, whereas the anti-inflammatory cytokine, IL-10, was induced upon HSP90 inhibition with AUY922. Mechanistically, we also noted a profound translocation of NFkB to the monocyte nucleus upon cytokine stimulation. Consistent with the effects on tissue factor expression, pro-inflammatory potential, and ROS generation, this translocation could be completely ablated with HSP90 inhibition. Importantly, HSP90 inhibitors significantly attenuated the LPS-activated monocyte -induced lung microvascular endothelial permeability. Conclusion Our data suggest that Hsp90 inhibitors significantly reduced the both pro-inflammatory and pro-coagulatory potential of PBMCs from patients with SCD. These results thus position HSP90 as a potential master regulator of hemostasis, endothelial cell permeability, and thus suggest that HSP90 is an attractive therapeutic target in patients with SCD. Disclosures: Kutlar: Celgene Corporation: Research Funding. Meiler:Celgene Corporation: Research Funding.
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Wolf, Yochai, Anat Shemer, Michal Polonsky, Mor Gross, Alexander Mildner, Simon Yona, Eyal David, et al. "Autonomous TNF is critical for in vivo monocyte survival in steady state and inflammation." Journal of Experimental Medicine 214, no. 4 (March 22, 2017): 905–17. http://dx.doi.org/10.1084/jem.20160499.
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Monocytes are circulating mononuclear phagocytes, poised to extravasate to sites of inflammation and differentiate into monocyte-derived macrophages and dendritic cells. Tumor necrosis factor (TNF) and its receptors are up-regulated during monopoiesis and expressed by circulating monocytes, as well as effector monocytes infiltrating certain sites of inflammation, such as the spinal cord, during experimental autoimmune encephalomyelitis (EAE). In this study, using competitive in vitro and in vivo assays, we show that monocytes deficient for TNF or TNF receptors are outcompeted by their wild-type counterpart. Moreover, monocyte-autonomous TNF is critical for the function of these cells, as TNF ablation in monocytes/macrophages, but not in microglia, delayed the onset of EAE in challenged animals and was associated with reduced acute spinal cord infiltration of Ly6Chi effector monocytes. Collectively, our data reveal a previously unappreciated critical cell-autonomous role of TNF on monocytes for their survival, maintenance, and function.
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Noraz, Nelly, Janet L. Lathey, and Stephen A. Spector. "Human Cytomegalovirus-Associated Immunosuppression Is Mediated Through Interferon-α." Blood 89, no. 7 (April 1, 1997): 2443–52. http://dx.doi.org/10.1182/blood.v89.7.2443.
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Abstract Human cytomegalovirus (HCMV) infections are commonly associated with a generalized immunologic hyporesponsiveness. The present study was designed to evaluate the potential mechanisms of HCMV-associated immunosuppression. In our initial experiments, monocytes in peripheral blood mononuclear cells (PBMCs) exposed to cell-free HCMV appeared morphologically less differentiated than monocytes in PBMCs exposed to a mock preparation. These morphologic changes were closely correlated with a decrease in monocyte oxidative activity and occurred under noncytopathic conditions. HCMV-associated suppression of monocyte differentiation did not require virus replication, occurred in PBMCs from either HCMV seropositive or seronegative donors, and required HCMV interaction with the nonadherent cells. An HCMV-induced soluble factor was found to not only reproduce the identical changes in purified monocytes but to inhibit the phagocytic activity of these cells. Additionally, the HCMV-induced factor accounted for a generalized defect in the ability of PBMCs to proliferate in response to mitogens and recall antigens. In subsequent experiments, interferon-α (IFN-α) was identified as the soluble factor involved in these immunosuppressive effects. Thus, PBMCs, when exposed to HCMV, produce a soluble factor, identified as IFN-α, that appears to be an important mediator of immunosuppression associated with HCMV infection.