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1
Rabkin, Charles S., Quan-en Yang, James J. Goedert, Giao Nguyen, Hiroaki Mitsuya, and Shizuko Sei. "Chemokine and Chemokine Receptor Gene Variants and Risk of Non-Hodgkin’s Lymphoma in Human Immunodeficiency Virus-1–Infected Individuals." Blood 93, no. 6 (March 15, 1999): 1838–42. http://dx.doi.org/10.1182/blood.v93.6.1838.406k39_1838_1842.
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Normal B-lymphocyte maturation and proliferation are regulated by chemotactic cytokines (chemokines), and genetic polymorphisms in chemokines and chemokine receptors modify progression of human immunodeficiency virus-1 (HIV-1) infection. Therefore, 746 HIV-1–infected persons were examined for associations of previously described stromal cell-derived factor 1 (SDF-1) chemokine and CCR5 and CCR2 chemokine receptor gene variants with the risk of B-cell non-Hodgkin’s lymphoma (NHL). The SDF1-3′A chemokine variant, which is carried by 37% of whites and 11% of blacks, was associated with approximate doubling of the NHL risk in heterozygotes and roughly a fourfold increase in homozygotes. After a median follow-up of 11.7 years, NHL developed in 6 (19%) of 30 SDF1-3′A/3′A homozygotes and 22 (10%) of 202 SDF1-+/3′A heterozygotes, compared with 24 (5%) of 514 wild-type subjects. The acquired immunodeficiency syndrome (AIDS)-protective chemokine receptor variant CCR5-▵32 was highly protective against NHL, whereas the AIDS-protective variant CCR2-64I had no significant effect. Racial differences in SDF1-3′A frequency may contribute to the lower risk of HIV-1–associated NHL in blacks compared with whites. SDF-1 genotyping of HIV-1–infected patients may identify subgroups warranting enhanced monitoring and targeted interventions to reduce the risk of NHL.
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Ho, Teik K., X. Shiwen, D. Abraham, J. Tsui, and D. Baker. "Stromal-Cell-Derived Factor-1 (SDF-1)/CXCL12 as Potential Target of Therapeutic Angiogenesis in Critical Leg Ischaemia." Cardiology Research and Practice 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/143209.
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In the Western world, peripheral vascular disease (PVD) has a high prevalence with high morbidity and mortality. In a large percentage of these patients, lower limb amputation is still required. Studies of ischaemic skeletal muscle disclosed evidence of endogenous angiogenesis and adaptive skeletal muscle metabolic changes in response to hypoxia. Chemokines are potent chemoattractant cytokines that regulate leukocyte trafficking in homeostatic and inflammatory processes. More than 50 different chemokines and 20 different chemokine receptors have been cloned. The chemokine stromal-cell-derived factor-1 (SDF-1 aka CXCL12) is a constitutively expressed and inducible chemokine that regulates multiple physiological processes, including embryonic development and organ homeostasis. The biologic effects of SDF-1 are mediated by chemokine receptor CXCR4, a 352 amino acid rhodopsin-like transmembrane-specific G protein-coupled receptor (GPCR). There is evidence that the administration of SDF-1 increases blood flow and perfusion via recruitment of endothelial progenitor cells (EPCs). This review will focus on the role of the SDF-1/CXCR4 system in the pathophysiology of PVD and discuss their potential as therapeutic targets for PVD.
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Stumm, Ralf, and Volker Höllt. "CXC chemokine receptor 4 regulates neuronal migration and axonal pathfinding in the developing nervous system: implications for neuronal regeneration in the adult brain." Journal of Molecular Endocrinology 38, no. 3 (March 2007): 377–82. http://dx.doi.org/10.1677/jme-06-0032.
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Chemotactic cytokines (chemokines) are small secreted proteins that control leukocyte trafficking in immune organs. Chemokines which are induced in the brain during conditions of inflammation play a role in the local immune response. Recently, it has been established in the rodent brain that distinct chemokines and chemokine receptors are constitutively expressed by neurons and that these chemokines modulate neuronal functions. The CXC motif chemokine stromal cell-derived factor-1 (SDF-1), CXCL12 together with its cognate receptor CXCR4 represents the best-characterized neuronal chemokine system. Transwell migration assays with neuronal precursors, pharmacological manipulation of CXCR4 signaling in embryonic brain explants, and histochemical studies of SDF-1- or CXCR4-deficient mouse embryos provide proof that SDF-1 directs neuronal migration and axonal pathfinding in the developing nervous system. In the adult brain, SDF-1 is thought to influence neurogenesis as well as recruitment of brain resident and non-resident circulating cells toward sites of lesion. The present review summarizes patterns and functions of the SDF-1/CXCR4 system in the rodent brain with a focus on the developing and adult cerebral cortex.
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Tilton, Bettina, Liza Ho, Estelle Oberlin, Pius Loetscher, Françoise Baleux, Ian Clark-Lewis, and Marcus Thelen. "Signal Transduction by Cxc Chemokine Receptor 4." Journal of Experimental Medicine 192, no. 3 (July 31, 2000): 313–24. http://dx.doi.org/10.1084/jem.192.3.313.
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We report that stromal cell–derived factor (SDF)-1 has the remarkable capacity to induce sustained signaling through CXC chemokine receptor 4 (CXCR4). In contrast to other chemokines, such as monocyte chemotactic protein 1 (CC chemokine receptor 2 [CCR2]), macrophage inflammatory protein 1β (CCR5), liver and activation-regulated chemokine (LARC [CCR6]), Epstein-Barr virus–induced molecule 1 ligand chemokine (ELC [CCR7]), and IP10 (CXCR3), SDF-1 stimulates the prolonged activation of protein kinase B and extracellular signal–regulated kinase (ERK)-2. Activation of protein kinase B is reversed by displacement of SDF-1 from CXCR4 or inhibition of phosphatidylinositol 3-kinase. Although increasing concentrations of SDF-1 enhance CXCR4 internalization, kinase activation is prolonged. In addition, restimulation yields >60% of initial protein kinase B activity, indicating that the remaining receptors are not desensitized. Furthermore, activation is prolonged by inhibiting SDF-1 degradation. The sustained activation of cell survival and mitogenic pathways may account for the unique role of SDF-1 and CXCR4 in embryogenesis and lymphopoiesis.
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Perks, Bea. "SDF-1: the repulsive chemokine." Immunology Today 21, no. 7 (July 2000): 309. http://dx.doi.org/10.1016/s0167-5699(00)01685-6.
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Kowalska, M. Anna, Mariusz Z. Ratajczak, Marcin Majka, Jianguo Jin, Satya Kunapuli, Lawrence Brass, and Mortimer Poncz. "Stromal cell–derived factor-1 and macrophage-derived chemokine: 2 chemokines that activate platelets." Blood 96, no. 1 (July 1, 2000): 50–57. http://dx.doi.org/10.1182/blood.v96.1.50.
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Abstract Platelets play roles in both thrombosis and inflammation, and chemokines that are released at sites of inflammation could potentially activate platelets. Among the chemokine receptors expressed on platelets, the CXCR4 is the receptor for chemokine stromal cell-derived factor-1 (SDF-1), and the CCR4 is the receptor for macrophage-derived chemokine (MDC). Of the chemokines tested, SDF-1 and MDC were the only 2 that activated platelets. Both are weak agonists, but they enhanced response to low-dose adenosine 5′-diphosphate (ADP), epinephrine, or serotonin. When SDF-1 and MDC were added together, full and brisk platelet aggregation occurred. Platelet activation by these 2 chemokines appears to involve distinct pathways: SDF-1 inhibited an increase in cyclic adenosine monophosphate (cAMP) following prostaglandin (PG) I2, while MDC had no effect. In contrast, MDC, but not SDF-1, lead to Ca++mobilization by platelets. Further, second-wave aggregation induced by MDC in platelet-rich plasma was inhibited by aspirin, ADP scavenger creatine phosphate/creative phosphokinase (CP/CPK), and ARL-66096, an antagonist of the ADP P2TAC receptor involved in adenylyl cyclase inhibition. But the aggregation was not affected by A3P5PS, an inhibitor of the ADP P2Y receptor. SDF-1–induced aggregation was inhibited by aspirin, but it was only slightly affected by CP/CPK, ARL-66096, or A3P5PS. Finally, the presence of chemokines in platelets was determined. Reverse transcriptase–polymerase chain reaction studies with platelet RNA did not detect the presence of SDF-1 or MDC. In summary, SDF-1 and MDC are platelet agonists that activate distinct intracellular pathways. Their importance in the development of thrombosis at sites of inflammation needs to be further evaluated.
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Kowalska, M. Anna, Mariusz Z. Ratajczak, Marcin Majka, Jianguo Jin, Satya Kunapuli, Lawrence Brass, and Mortimer Poncz. "Stromal cell–derived factor-1 and macrophage-derived chemokine: 2 chemokines that activate platelets." Blood 96, no. 1 (July 1, 2000): 50–57. http://dx.doi.org/10.1182/blood.v96.1.50.013k40_50_57.
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Platelets play roles in both thrombosis and inflammation, and chemokines that are released at sites of inflammation could potentially activate platelets. Among the chemokine receptors expressed on platelets, the CXCR4 is the receptor for chemokine stromal cell-derived factor-1 (SDF-1), and the CCR4 is the receptor for macrophage-derived chemokine (MDC). Of the chemokines tested, SDF-1 and MDC were the only 2 that activated platelets. Both are weak agonists, but they enhanced response to low-dose adenosine 5′-diphosphate (ADP), epinephrine, or serotonin. When SDF-1 and MDC were added together, full and brisk platelet aggregation occurred. Platelet activation by these 2 chemokines appears to involve distinct pathways: SDF-1 inhibited an increase in cyclic adenosine monophosphate (cAMP) following prostaglandin (PG) I2, while MDC had no effect. In contrast, MDC, but not SDF-1, lead to Ca++mobilization by platelets. Further, second-wave aggregation induced by MDC in platelet-rich plasma was inhibited by aspirin, ADP scavenger creatine phosphate/creative phosphokinase (CP/CPK), and ARL-66096, an antagonist of the ADP P2TAC receptor involved in adenylyl cyclase inhibition. But the aggregation was not affected by A3P5PS, an inhibitor of the ADP P2Y receptor. SDF-1–induced aggregation was inhibited by aspirin, but it was only slightly affected by CP/CPK, ARL-66096, or A3P5PS. Finally, the presence of chemokines in platelets was determined. Reverse transcriptase–polymerase chain reaction studies with platelet RNA did not detect the presence of SDF-1 or MDC. In summary, SDF-1 and MDC are platelet agonists that activate distinct intracellular pathways. Their importance in the development of thrombosis at sites of inflammation needs to be further evaluated.
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Maréchal, Valérie, Fernando Arenzana-Seisdedos, Jean-Michel Heard, and Olivier Schwartz. "Opposite Effects of SDF-1 on Human Immunodeficiency Virus Type 1 Replication." Journal of Virology 73, no. 5 (May 1, 1999): 3608–15. http://dx.doi.org/10.1128/jvi.73.5.3608-3615.1999.
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ABSTRACT The α-chemokine SDF-1 binds CXCR4, a coreceptor for human immunodeficiency virus type 1 (HIV-1), and inhibits viral entry mediated by this receptor. Since chemokines are potent chemoattractants and activators of leukocytes, we examined whether the stimulation of HIV target cells by SDF-1 affects the replication of virus with different tropisms. We observed that SDF-1 inhibited the entry of X4 strains and increased the infectivity of particles bearing either a CCR5-tropic HIV-1 envelope or a vesicular stomatitis virus G envelope. In contrast to the inhibitory effect of SDF-1 on X4 strains, which is at the level of entry, the stimulatory effect does not involve envelope-receptor interactions or proviral DNA synthesis. Rather, we observed an increased ability of Tat to transactivate the HIV-1 long terminal repeat in the presence of the chemokine. Therefore, the effects of SDF-1 on the HIV-1 life cycle can be multiple and opposite, including both an inhibition of viral entry and a stimulation of proviral gene expression.
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Miura, Kohei, Shashi Uniyal, Mircea Leabu, Tamas Oravecz, Subrata Chakrabarti, Vincent L. Morris, and Bosco M. C. Chan. "Chemokine receptor CXCR4-β1 integrin axis mediates tumorigenesis of osteosarcoma HOS cells." Biochemistry and Cell Biology 83, no. 1 (February 1, 2005): 36–48. http://dx.doi.org/10.1139/o04-106.
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It is known that β1 integrins mediate the migratory response of cells to chemokine stimulation. Also, both β1 integrins and chemokines have roles in tumor development. In the present study, the β1 integrin-chemokine axis is assessed using human osteosarcoma (HOS) transfectant cells expressing the CXCR4 receptor for chemokine SDF-1 (CXCL12). We first identified in vitro the specific β1 integrins that mediated the migratory response to SDF-1 stimulation. Results showed that on collagen type I and laminin, the chemotactic response to SDF-1 was predominantly mediated by α2β1 integrin. On fibronectin, SDF-1-stimulated chemotaxis involved both α4β1 and α5β1 integrins. A comparison of the transfectant clones expressing CXCR4 at low, intermediate, and high levels and the control transfectant revealed that the transfectant clones migratory response in vitro and their ability to form tumors in vivo was related to their levels of CXCR4 expression. In addition, treatment by injection with mAbs to CXCR4, integrin α2β1, or integrin α5β1 effectively inhibited the growth of HOS-CXCR4 transfectant cells in vivo. Therefore, our results show that the β1 integrins that mediated the migratory response were also functionally linked to the enhanced tumor growth of CXCR4-expressing HOS transfectant cells.Key words: integrins, chemokines, chemotaxis, osteosarcoma, tumorigenesis.
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Gear, Adrian R. L., Sudawadee Suttitanamongkol, Delia Viisoreanu, Renata K. Polanowska-Grabowska, Sanghamitra Raha, and David Camerini. "Adenosine diphosphate strongly potentiates the ability of the chemokines MDC, TARC, and SDF-1 to stimulate platelet function." Blood 97, no. 4 (February 15, 2001): 937–45. http://dx.doi.org/10.1182/blood.v97.4.937.
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Abstract Platelet activation is normally induced by primary agonists such as adenosine diphosphate (ADP), thrombin, and collagen, whereas other agonists, such as epinephrine, can play important accessory roles. It is now reported that the macrophage-derived chemokine (MDC), thymus activation–regulated chemokine (TARC), and stromal cell–derived factor one (SDF-1) are highly effective activators of platelet function under a variety of conditions, stimulating platelet shape change, aggregation, and adhesion to collagen or fibrinogen. Chemokine-mediated platelet activation was rapid and maximal (less than 5 seconds) under arterial flow conditions and depended strongly on the presence of low levels of primary agonists such as ADP or thrombin. Concentrations of ADP (0.05-0.25 μM) or thrombin (0.005-0.02 U/mL) that induced minimal aggregation caused major aggregation acting in combination with the chemokines. The ability of apyrase to block chemokine-dependent aggregation or adhesion was consistent with an important role for ADP. Chemokine-stimulated aggregation was also insensitive to indomethacin, suggesting that the activation of cyclo-oxygenase is not involved. TARC, MDC, and SDF-1 increased intracellular calcium concentrations [Ca2+]iwhen combined with low levels of ADP. The MDC and TARC receptor CCR4 was expressed on platelets, and an anti-CCR4 antibody blocked aggregation induced by TARC or MDC. Treatment of platelets with SDF-1 and MDC rapidly exposed P-selectin (CD62P) on the cell surface but did not induce the secretion of serotonin. These findings suggest that the chemokines MDC, TARC, and SDF-1, which may be produced during inflammatory responses, coupled with low levels of ADP or thrombin, can serve as strong stimuli for activating platelet function.
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Ray, Paramita, Sarah A. Lewin, Laura Anne Mihalko, Sasha-Cai Lesher-Perez, Shuichi Takayama, Kathryn E. Luker, and Gary D. Luker. "Secreted CXCL12 (SDF-1) forms dimers under physiological conditions." Biochemical Journal 442, no. 2 (February 13, 2012): 433–42. http://dx.doi.org/10.1042/bj20111341.
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Chemokine CXCL12 (CXC chemokine ligand 12) signalling through CXCR (CXC chemokine receptor) 4 and CXCR7 has essential functions in development and underlies diseases including cancer, atherosclerosis and autoimmunity. Chemokines may form homodimers that regulate receptor binding and signalling, but previous studies with synthetic CXCL12 have produced conflicting evidence for homodimerization. We used bioluminescence imaging with GL (Gaussia luciferase) fusions to investigate dimerization of CXCL12 secreted from mammalian cells. Using column chromatography and GL complementation, we established that CXCL12 was secreted from mammalian cells as both monomers and dimers. Secreted CXCL12 also formed homodimers in the extracellular space. Monomeric CXCL12 preferentially activated CXCR4 signalling through Gαi and Akt, whereas dimeric CXCL12 more effectively promoted recruitment of β-arrestin 2 to CXCR4 and chemotaxis of CXCR4-expressing breast cancer cells. We also showed that CXCR7 preferentially sequestered monomeric CXCL12 from the extracellular space and had minimal effects on dimeric CXCL12 in cell-based assays and an orthotopic tumour xenograft model of human breast cancer. These studies establish that CXCL12 secreted from mammalian cells forms homodimers under physiological conditions. Since monomeric and dimeric CXCL12 have distinct effects on cell signalling and function, our results have important implications for ongoing efforts to target CXCL12 pathways for therapy.
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Kim, Chang H., Cheng-Kui Qu, Giao Hangoc, Scott Cooper, Naoyuki Anzai, Gen-Sheng Feng, and Hal E. Broxmeyer. "Abnormal Chemokine-Induced Responses of Immature and Mature Hematopoietic Cells from Motheaten Mice Implicate the Protein Tyrosine Phosphatase Shp-1 in Chemokine Responses." Journal of Experimental Medicine 190, no. 5 (September 6, 1999): 681–90. http://dx.doi.org/10.1084/jem.190.5.681.
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Chemokines regulate a number of biological processes, including trafficking of diverse leukocytes and proliferation of myeloid progenitor cells. SHP-1 (Src homology 2 domain tyrosine phosphatase 1), a phosphotyrosine phosphatase, is considered an important regulator of signaling for a number of cytokine receptors. Since specific tyrosine phosphorylation of proteins is important for biological activities induced by chemokines, we examined the role of SHP-1 in functions of chemokines using viable motheaten (mev/mev) mice that were deficient in SHP-1. Chemotactic responses to stromal call–derived factor 1 (SDF-1), a CXC chemokine, were enhanced with bone marrow myeloid progenitor cells as well as macrophages, T cells, and B cells from mev/mev versus wild-type (+/+) mice. SDF-1–dependent actin polymerization and activation of mitogen-activated protein kinases were also greater in mev/mev versus +/+ cells. In contrast, immature subsets of mev/mev bone marrow myeloid progenitors were resistant to effects of a number of chemokines that suppressed proliferation of +/+ progenitors. These altered chemokine responses did not appear to be due to enhanced expression of CXCR4 or lack of chemokine receptor expression. However, expression of some chemokine receptors (CCR1, CCR2, CCR3, and CXCR2) was significantly enhanced in mev/mev T cells. Our results implicate SHP-1 involvement in a number of different chemokine-induced biological activities.
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Guessous, Fadila, Marek Marcinkiewicz, Renata Polanowska-Grabowska, Sudawadee Kongkhum, Daniel Heatherly, Tom Obrig, and Adrian R. L. Gear. "Shiga Toxin 2 and Lipopolysaccharide Induce Human Microvascular Endothelial Cells To Release Chemokines and Factors That Stimulate Platelet Function." Infection and Immunity 73, no. 12 (December 2005): 8306–16. http://dx.doi.org/10.1128/iai.73.12.8306-8316.2005.
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ABSTRACT Shiga toxins (Stxs) produced by Shigella dysenteriae type 1 and enterohemorrhagic Escherichia coli are the most common cause of hemolytic-uremic syndrome (HUS). It is well established that vascular endothelial cells, mainly those located in the renal microvasculature, are targets for Stxs. The aim of the present research was to evaluate whether E. coli-derived Shiga toxin 2 (Stx2) incubated with human microvascular endothelial cells (HMEC-1) induces release of chemokines and other factors that might stimulate platelet function. HMEC-1 were exposed for 24 h in vitro to Stx2, lipopolysaccharide (LPS), or the Stx2-LPS combination, and chemokine production was assessed by immunoassay. More interleukin-8 was released than stromal cell-derived factor 1α (SDF-1α) or SDF-1β and RANTES. The Stx2-LPS combination potentiated chemokine release, but Stx2 alone caused more release of SDF-1α at 24 h than LPS or Stx2-LPS did. In the presence of low ADP levels, HMEC-1 supernatants activated platelet function assessed by classical aggregometry, single-particle counting, granule secretion, P-selectin exposure, and the formation of platelet-monocyte aggregates. Supernatants from HMEC-1 exposed only to Stx2 exhibited enhanced exposure of platelet P-selectin and platelet-THP-1 cell interactions. Blockade of platelet cyclooxygenase by indomethacin prevented functional activation. The chemokine RANTES enhanced platelet aggregation induced by SDF-1α, macrophage-derived chemokine, or thymus and activation-regulated chemokine in the presence of very low ADP levels. These data support the hypothesis that microvascular endothelial cells exposed to E. coli O157:H7-derived Stx2 and LPS release chemokines and other factors, which when combined with low levels of primary agonists, such as ADP, cause platelet activation and promote the renal thrombosis associated with HUS.
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Vanbervliet, Béatrice, Nathalie Bendriss-Vermare, Catherine Massacrier, Bernhard Homey, Odette de Bouteiller, Francine Brière, Giorgio Trinchieri, and Christophe Caux. "The Inducible CXCR3 Ligands Control Plasmacytoid Dendritic Cell Responsiveness to the Constitutive Chemokine Stromal Cell–derived Factor 1 (SDF-1)/CXCL12." Journal of Experimental Medicine 198, no. 5 (September 1, 2003): 823–30. http://dx.doi.org/10.1084/jem.20020437.
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The recruitment of selected dendritic cell (DC) subtypes conditions the class of the immune response. Here we show that the migration of human plasmacytoid DCs (pDCs), the blood natural interferon α–producing cells, is induced upon the collective action of inducible and constitutive chemokines. Despite expression of very high levels of CXCR3, pDCs do not respond efficiently to CXCR3 ligands. However, they migrate in response to the constitutive chemokine stromal cell–derived factor 1 (SDF-1)/CXCL12 and CXCR3 ligands synergize with SDF-1/CXCL12 to induce pDC migration. This synergy reflects a sensitizing effect of CXCR3 ligands, which, independently of a gradient and chemoattraction, decrease by 20–50-fold the threshold of sensitivity to SDF-1/CXCL12. Thus, the ability of the constitutive chemokine SDF-1/CXCL12 to induce pDC recruitment might be controlled by CXCR3 ligands released during inflammation such as in virus infection. SDF-1/CXCL12 and the CXCR3 ligands Mig/CXCL9 and ITAC/CXCL1 display adjacent expression both in secondary lymphoid organs and in inflamed epithelium from virus-induced pathologic lesions. Because pDCs express both the lymph node homing molecule l-selectin and the cutaneous homing molecule cutaneous lymphocyte antigen, the cooperation between inducible CXCR3 ligands and constitutive SDF-1/CXCL12 may regulate recruitment of pDCs either in lymph nodes or at peripheral sites of inflammation.
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Zhou, Yan, Peter H. Larsen, Chunhai Hao, and V. Wee Yong. "CXCR4 Is a Major Chemokine Receptor on Glioma Cells and Mediates Their Survival." Journal of Biological Chemistry 277, no. 51 (October 17, 2002): 49481–87. http://dx.doi.org/10.1074/jbc.m206222200.
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Chemokines were described originally in the context of providing migrational cues for leukocytes. They are now known to have broader activities, including those that favor tumor growth. We addressed whether and which chemokines may be important promoters of the growth of the incurable brain neoplasm, malignant gliomas. Analyses of 16 human glioma lines for the expression of chemokine receptors belonging to the CXCR and CCR series revealed low to negligible levels of all receptors, with the exception of CXCR4 that was expressed by 13 of 16 lines. All six resected human glioma specimens showed similarly high CXCR4 expression. The CXCR4 on glioma lines is a signaling receptor in that its agonist, stromal cell-derived factor-1 (SDF-1; CXCL12), produced rapid phosphorylation of mitogen-activated protein kinases. Furthermore, SDF-1 induced the phosphorylation of Akt (protein kinase B), a kinase associated with survival, and prevented the apoptosis of glioma cells when serum was withdrawn from the culture medium. SDF-1 also mediated glioma chemotaxis, in accordance with this better known role of chemokines. We conclude that glioma cells express a predominant chemokine receptor, CXCR4, and that this functions to regulate survival in part through activating pathways such as Akt.
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Casamayor-Pallejà, Montserrat, Paul Mondière, Ali Amara, Chantal Bella, Marie-Caroline Dieu-Nosjean, Christophe Caux, and Thierry Defrance. "Expression of macrophage inflammatory protein-3α, stromal cell–derived factor-1, and B-cell–attracting chemokine-1 identifies the tonsil crypt as an attractive site for B cells." Blood 97, no. 12 (June 15, 2001): 3992–94. http://dx.doi.org/10.1182/blood.v97.12.3992.
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The expression of 3 lymphoid chemokines—macrophage inflammatory protein-3α (MIP-3α), stromal cell–derived factor-1 (SDF-1), and B-cell–attracting chemokine-1 (BCA-1)—in the tonsil and the possible correlation between their sites of expression and B-cell localization within this tissue were studied. The results show that all 3 chemokines are produced in the crypts but differ by the nature of the cells that produce them and their location within the crypt. SDF-1 and MIP-3α are produced by epithelial cells, but their secretion is mutually exclusive. Both MIP-3α– and SDF-1–expressing cells are in close contact with memory B cells. By contrast, BCA-1–producing cells in the crypt are not epithelial and form clusters colocalized with plasma cells. Altogether, these data suggest that the chemokines produced in the tonsillar crypt may (1) attract memory B cells to antigen and (2) recruit and retain plasma cells and memory B cells within the supportive epithelial microenvironment of the crypt.
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Yonezawa, Akihito, Toshiyuki Hori, Akifumi Takaori-Kondo, Rinpei Morita, and Takashi Uchiyama. "Replacement of the V3 Region of gp120 with SDF-1 Preserves the Infectivity of T-Cell Line-Tropic Human Immunodeficiency Virus Type 1." Journal of Virology 75, no. 9 (May 1, 2001): 4258–67. http://dx.doi.org/10.1128/jvi.75.9.4258-4267.2001.
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ABSTRACT Interaction between the human immunodeficiency virus type 1 (HIV-1) envelope and the relevant chemokine receptors is crucial for subsequent membrane fusion and viral entry. Although the V3 region of gp120 is known to determine the cell tropism as well as the coreceptor usage, the significance of the binding of the V3 region to the chemokine receptor has not been fully understood. To address this issue, we adopted the pseudotyped virus infection assay in which the V3 region of the T-cell line-tropic (T-tropic) NL4-3 envelope was replaced with a portion of stromal cell-derived factor 1 (SDF-1), the ligand of CXCR4. The V3 region of the NL4-3 envelope expression vector was replaced with three different stretches of SDF-1 cDNA. Expression of each chimeric envelope protein was confirmed by immunoprecipitation and Western blotting. Luciferase reporter viruses were prepared by cotransfection of the pNL4-3.Luc.E−R− vector and each chimeric envelope expression vector, and the infection assay was then carried out. We showed that pseudotyped viruses with one of the chimeric envelopes, NL4-3/SDF1-51, could infect U87.CD4.CXCR4 but not U87.CD4 or U87.CXCR4 cells and that this infection was inhibited by the ligand of CXCR4, SDF-1β, by anti-human SDF-1 antibody, or by an anti-CD4 antibody, Leu3a, in a dose-dependent manner. Furthermore, chimeric NL4-3/SDF1-51 gp120 significantly inhibited binding of labeled SDF-1 to CXCR4. It was suggested that replacement of the V3 region of the NL4-3 envelope with SDF-1 preserved the CD4-dependent infectivity of T-tropic HIV-1. These results indicate that binding between the V3 region and the relevant coreceptor is important for viral entry, whether its amino acid sequence is indigenous to the virus or not.
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Broxmeyer, Hal E., Timothy B. Campbell, Scott Cooper, and Giao Hangoc. "Inhibition/Depletion of CD26/DPPIV Enhances Survival Promoting Activity of SDF-1/CXCL12 and Myelosuppressive Activities of Inhibitory Chemokines on Hematopoietic Progenitor Cells." Blood 110, no. 11 (November 16, 2007): 610. http://dx.doi.org/10.1182/blood.v110.11.610.610.
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Abstract Hematopoiesis is regulated by an interacting network of cells, cell surface proteins, and cytokines/chemokines. CD26 is a cell surface peptidase (Dipeptidylpeptidase IV) that cleaves the N-terminal dipeptide from various substrates, such as selected members of the chemokine family, at a penultimate proline or alanine residue. CD26 is expressed by hematopoietic stem (HSCs) and progenitor (HPCs) cells, as well as a number of other immature and mature cell types. By truncating the chemokine stromal derived factor-1 (SDF-1/CXCL12), CD26 has been implicated in modulation of chemotaxis, homing and mobilization of HSCs/HPCs. Inhibition of CD26 by small peptides such as Diprotin A, or deletion of CD26 (e.g. cells from CD26 −/− mice or siRNA induced decreases in CD26) manifests in enhanced chemotaxis of HSCs/HPCs to SDF-1/CXCL12, and enhanced homing/engraftment of HSCs in mice. We hypothesized that inhibition of CD26 would manifest in enhanced activities of other functions of SDF-1/CXCL12. Moreover, since CD26 truncates other chemokines, we reasoned that inhibition of CD26 would enhance hematopoietic activities of these other chemokines. SDF-1/CXCL12 enhances survival/anti-apoptosis of HSCs/HPCs. We now report that pretreating mouse bone marrow cells (BMCs) with Diprotin A, whether or not the cells were washed prior to plating, or use of CD26 −/− mouse BMCs in a delayed addition of growth factor setting resulted in enhanced survival of HPCs at concentrations of SDF-1/CXCL12 at least 100-fold less than that which would normally manifest survival enhancing activities. We also assessed the influence of CD26 inhibition or deletion on the myelosuppressive effects of chemokines with known inhibitory activity and those that had not previously shown this activity. Suppression/deletion of CD26 on mouse BMCs greatly enhanced the activity of myelosuppressive chemokines such as is MIP-1α/CCL3 and GCP-2/CXCL6, such that these chemokines demonstrated inhibition of colony formation by multi-cytokine stimulated CFU-GM, BFU-E, and CFU-GEMM, at concentrations of these chemokines at least 100-fold less than that possible without inhibition/deletion of CD26. However, CD26 inhibition/deletion did not change the activity of non-myelosuppressive chemokines such as MIP-1β/CCL4, RANTES/CCL5, or SDF-1/CXCL12 into suppressive molecules. Since survival of HPCs is related to the cell cycle status of HPCs, such that slow or non-cycling HPCs are less sensitive to stresses leading to apoptosis, the enhanced activity of SDF-1/CXCL12 and the myelosuppressive chemokines (which are specifically inhibitory to HPCs in S-phase of the cell cycle) may act as coordinating separate signals to protect HPCs from stress-induced apoptosis. These results demonstrate that CD26 plays a modulating role on different hematopoietic activities mediated by chemokines, and this role for CD26 should be taken into account when describing models of chemokine effects on hematopoiesis, and attempts at modifying these effects.
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Tan, Suiyi, Wenjuan Li, Zhaofeng Li, Yujing Li, Jiangyan Luo, Liangzhentian Yu, Jie Yang, et al. "A Novel CXCR4 Targeting Protein SDF-1/54 as an HIV-1 Entry Inhibitor." Viruses 11, no. 9 (September 18, 2019): 874. http://dx.doi.org/10.3390/v11090874.
Full textAbstract:
CXC chemokine receptor 4 (CXCR4) is a co-receptor for HIV-1 entry into target cells. Its natural ligand, the chemokine SDF-1, inhibits viral entry mediated by this receptor. However, the broad expression pattern of CXCR4 and its critical roles in various physiological and pathological processes indicate that the direct application of SDF-1 as an entry inhibitor might have severe consequences. Previously, we constructed an effective SDF-1 mutant, SDF-1/54, by deleting the α-helix of the C-terminal functional region of SDF-1. Of note, SDF-1/54 shows remarkable decreased chemotoxic ability, but maintains a similar binding affinity to CXCR4, suggesting SDF-1/54 might better serve as a CXCR4 inhibitor. Here, we found that SDF-1/54 exhibited potent antiviral activity against various X4 HIV-1 strains, including the infectious clone HIV-1 NL4-3, laboratory-adapted strain HIV-1 IIIB, clinical isolates and even drug-resistant strains. By using time-of-addition assay, non-infectious and infectious cell–cell fusion assay and CXCR4 internalization assay, we demonstrated SDF-1/54 is an HIV-1 entry inhibitor. A combination of SDF-1/54 with several antiretroviral drugs exhibited potent synergistic anti-HIV-1 activity. Moreover, SDF-1/54 was stable and its anti-HIV-1 activity was not significantly affected by the presence of seminal fluid, vaginal fluid simulant and human serum albumin. SDF-1/54 showed limited in vitro cytotoxicity to lymphocytes and vaginal epithelial cells. Based on these findings, SDF-1/54 could have a therapeutic potential as an HIV-1 entry inhibitor.
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Cho, Sool Yeon, John Roboz, Mingjiang Xu, and Ronald Hoffman. "Primary Myelofibrosis Is Associated with Truncation of the Plasma Chemokine SDF-1." Blood 112, no. 11 (November 16, 2008): 3731. http://dx.doi.org/10.1182/blood.v112.11.3731.3731.
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Abstract Primary myelofibrosis (PMF) is a myeloproliferative disorder (MPD) characterized by abnormal cellular trafficking leading to constitutive mobilization of CD34+ cells. This abnormal trafficking has been associated with elevation of the plasma and marrow levels of the chemokine SDF-1 and reduced expression of its receptor CXCR4 by CD34+ cells. We have reported that plasma levels of matrix metalloproteinases (MMPs) and neutrophil elastase (NE) are elevated in the plasma of patients with PMF and polycythemia vera (PV). Such proteases are capable of degrading VCAM-1 and SDF-1 both of which function to retain CD34+ cells within the marrow (Xu et al. Blood, 105:4508, 2005). The elevation of SDF-1 both in the blood and marrow of PMF patients has been difficult to reconcile with the mobilization of CD34+ cells. It has been reported that several plasma proteases truncate SDF-1 by removing two or more amino acids from the N-terminal. The degradation of SDF-1 results in the generation of truncated forms of SDF-1 which can compete with the intact SDF-1 for CXCR4, possibly leading to the release of CD34+ cells from the marrow. We studied the truncating activities of dipeptidyl peptidase IV (CD26), NE, MMP, and cathepsin G (CG). We characterized the truncated form SDF-1 in vitro upon incubation of recombinant SDF-1 with each of these individual proteases and analyzed the truncated SDF-1 forms in the plasma of patients with MPD. Electrospray ionization mass spectrometry was used to determine characteristic multiply charged ions from the truncation products and, to search for these products directly in MPD patient plasma by monitoring up to 15 representative masses (obtained in incubation experiments). We confirmed the expected molecular mass of SDF-1, using the masses of the +6, +7, +8 multiply charged ions. The estimated quantity of SDF-1 in normal plasma (n=3) was 6 ng/mL. The corresponding amount in plasma from patients with PV (n=5) and PMF (n=3) were 2 to 5-fold greater. We have utilized the same approach to determine the degree of SDF-1 truncation due to CD26 (removal of two amino acids (aa), NE (removal of 3 aa), MMP (removal of 4 aa), and CG (removal of 5 aa, also yielded products corresponding to the removal of 2, 3 and 4 aa). Based on these results, we have monitored these representative masses to search for the truncated SDF-1 forms in MPD. No detectable levels of the truncated forms of SDF-1 was found in normal plasma (n=3), since the peaks were below the estimated detection limit of 500 pg/mL. By contrast, each of the truncated products was detected in the MPD plasma. Intact (full length) SDF-1 was present in MPD plasma, but the total quantity of the truncated forms was 3–4 fold greater than that of intact SDF-1. In the PV samples, the estimated quantity of each truncated SDF-1 form due to MMP, NE, and CD26 activity was similar (approx. 12 ng/mL); the corresponding amounts in the PMF plasma samples were approx. two-fold greater than that present in PV plasma. The quantity of the 5 aa truncated form was 19 ng/mL in PV and 53 ng/mL in PMF samples. These data suggest that proteases present in the plasma of MPD patients digest SDF-1 leading to the generation of several truncated forms of SDF-1. We hypothesize that these truncated forms of SDF-1 likely compete with the full length form of SDF-1 for CXCR4 expression by CD34+ cells leading to the release of CD34+ cells from the marrow and their constitutive mobilization.
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Salvucci, Ombretta, Lei Yao, Sabrina Villalba, Agatha Sajewicz, Stefania Pittaluga, and Giovanna Tosato. "Regulation of endothelial cell branching morphogenesis by endogenous chemokine stromal-derived factor-1." Blood 99, no. 8 (April 15, 2002): 2703–11. http://dx.doi.org/10.1182/blood.v99.8.2703.
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Abstract The chemokine stromal-derived factor-1 (SDF-1) and its unique receptor, CXCR4, are required for normal cardiovascular development, but a critical role for SDF-1 in postnatal vascular remodeling and the mechanisms underlying SDF-1/CXCR-4 vasculogenesis are unclear. Here we show that SDF-1 is expressed by the vascular endothelium from selected healthy and tumor tissues. In vitro, primary endothelial cells constitutively express SDF-1 that is detected in the cytoplasm, on the cell surface, and in the culture supernatant. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) increase SDF-1 expression in endothelial cells. In functional studies, pertussis toxin and antibodies to SDF-1 or CXCR-4 disrupt extracellular matrix-dependent endothelial cell tube formation in vitro. This morphogenic process is associated with time-dependent modulation of surface CXCR-4 expression that changes from being diffuse to being polarized and subsequently lost. In vivo, pertussis toxin and neutralizing antibodies directed at SDF-1 inhibit growth factor–dependent neovascularization. These results indicate that SDF-1/CXCR-4 identifies VEGF- and bFGF-regulated autocrine signaling systems that are essential regulators of endothelial cell morphogenesis and angiogenesis.
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Burger, Jan A., Meike Burger, and Thomas J. Kipps. "Chronic Lymphocytic Leukemia B Cells Express Functional CXCR4 Chemokine Receptors That Mediate Spontaneous Migration Beneath Bone Marrow Stromal Cells." Blood 94, no. 11 (December 1, 1999): 3658–67. http://dx.doi.org/10.1182/blood.v94.11.3658.
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Abstract Chemokines play a central role for lymphocyte trafficking and homing. The mechanisms that direct the tissue localization of B cells from patients with chronic lymphocytic leukemia (B-CLL) are unknown. We found that CLL B cells express functional CXCR4 receptors for the chemokine stromal cell-derived factor-1 (SDF-1), as demonstrated by receptor endocytosis, calcium mobilization, and actin polymerization assays. Moreover, CLL B cells displayed chemotaxis to this chemokine that could be inhibited by monoclonal antibodies (MoAbs) against CXCR4, pertussis toxin, or Wortmannin, a phosphatidylinositol 3-kinase inhibitor. That this chemotaxis may be involved in the homing of CLL cells is argued by studies in which CLL B cells were cocultured with a murine marrow stromal cell line that secretes SDF-1. Within 2 hours, CLL B cells spontaneously migrated beneath such stromal cells in vitro (pseudoemperipolesis). This migration could be inhibited by pretreatment of CLL B cells with anti-CXCR4 MoAbs, SDF-1, or pertussis-toxin. Furthermore, we noted strong downmodulation of CXCR4 on CLL B cells that migrated into the stromal cell layer. These findings demonstrate that the chemokine receptor CXCR4 on CLL B cells plays a critical role for heterotypic adherence to marrow stromal cells and provide a new mechanism to account for the marrow infiltration by neoplastic B cells.
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Burger, Jan A., Meike Burger, and Thomas J. Kipps. "Chronic Lymphocytic Leukemia B Cells Express Functional CXCR4 Chemokine Receptors That Mediate Spontaneous Migration Beneath Bone Marrow Stromal Cells." Blood 94, no. 11 (December 1, 1999): 3658–67. http://dx.doi.org/10.1182/blood.v94.11.3658.423k11_3658_3667.
Full textAbstract:
Chemokines play a central role for lymphocyte trafficking and homing. The mechanisms that direct the tissue localization of B cells from patients with chronic lymphocytic leukemia (B-CLL) are unknown. We found that CLL B cells express functional CXCR4 receptors for the chemokine stromal cell-derived factor-1 (SDF-1), as demonstrated by receptor endocytosis, calcium mobilization, and actin polymerization assays. Moreover, CLL B cells displayed chemotaxis to this chemokine that could be inhibited by monoclonal antibodies (MoAbs) against CXCR4, pertussis toxin, or Wortmannin, a phosphatidylinositol 3-kinase inhibitor. That this chemotaxis may be involved in the homing of CLL cells is argued by studies in which CLL B cells were cocultured with a murine marrow stromal cell line that secretes SDF-1. Within 2 hours, CLL B cells spontaneously migrated beneath such stromal cells in vitro (pseudoemperipolesis). This migration could be inhibited by pretreatment of CLL B cells with anti-CXCR4 MoAbs, SDF-1, or pertussis-toxin. Furthermore, we noted strong downmodulation of CXCR4 on CLL B cells that migrated into the stromal cell layer. These findings demonstrate that the chemokine receptor CXCR4 on CLL B cells plays a critical role for heterotypic adherence to marrow stromal cells and provide a new mechanism to account for the marrow infiltration by neoplastic B cells.
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Russo, Giandomenico, Enrico Scala, Antonella Bresin, Elisabetta Caprini, Maria Cristina Picchio, Daniele Remotti, Gianluca Ragone, et al. "SDF-1-CXCR4 Signaling and Downregulation of CD26/Dipeptidyl-Peptidase IV Are Involved in Skin-Homing of Sezary Cells." Blood 106, no. 11 (November 16, 2005): 4489. http://dx.doi.org/10.1182/blood.v106.11.4489.4489.
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Abstract Sezary Syndrome (SS) is a rare form of Cutaneous T-Cell Lymphoma (CTCL) characterised by a distinct metastatic pattern mainly involving skin and blood. Chemokine and chemokine receptors have been implicated in the spreading process of many cancers including various forms of non-Hodgkin T-cell lymphomas (NHL). In this study we report that chemokine receptor CXCR4 is over-expressed by both circulating and skin-homing neoplastic T-lymphocytes of SS patients and is functionally active as demonstrated by the migration of freshly isolated Sezary (SzS) cells along the chemical gradient of its natural ligand SDF-1. To shed light on the regulation of CXCR4/SDF1 interaction, we also investigated the enzymatic activity of CD26/dipeptidylpeptidase IV (DPPIV) since SDF-1 is efficiently inactivated by CD26, in physiological condition.. This is of particular relevance because one of the hallmark of the circulating SzS cells is the loss of CD26 from the cell surface. We first demonstrated that the CD26 negative phenotype is similarly maintained also in the skin-homing neoplastic T lymphocytes; we then observed that the addition of exogenus soluble CD26 reduces the migratory response of SS cells to SDF-1 whereas the inhibition of the CD26 peptidase activity in Hut78, a CD26-positive CTCL cell line, enhances the SDF-1-induced migration of these cells. We finally showed that SS individuals exhibit a reduced activity of the soluble CD26 as revealed by the measurements performed on the patients derived plasma. Our findings suggest that the SDF-1-CXCR4 axis could play an important role in skin homing of SS through the regulatory activity of CD26.
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Suratt, Benjamin T., Joseph M. Petty, Scott K. Young, Kenneth C. Malcolm, Jonathan G. Lieber, Jerry A. Nick, Jose-Angel Gonzalo, Peter M. Henson, and G. Scott Worthen. "Role of the CXCR4/SDF-1 chemokine axis in circulating neutrophil homeostasis." Blood 104, no. 2 (July 15, 2004): 565–71. http://dx.doi.org/10.1182/blood-2003-10-3638.
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Abstract The bone marrow is the primary site for neutrophil production and release into the circulation. Because the CXC chemokine receptor-4/stromal derived factor-1 (CXCR4/SDF-1) axis plays a central role in the interactions of hematopoietic stem cells, lymphocytes, and developing neutrophils in the marrow, we investigated whether reciprocal CXCR4-dependent mechanisms might be involved in neutrophil release and subsequent return to the marrow following circulation. Neutralizing antibody to CXCR4 reduced marrow retention of infused neutrophils (45.7% ± 0.5% to 6.9% ± 0.5%) and was found to mobilize neutrophils from marrow (34.4% ± 4.4%). Neutrophil CXCR4 expression and SDF-1-induced calcium flux decreased with maturation and activation of the cells, corresponding to the decreased marrow homing associated with these characteristics in vivo. Infusion of the inflammatory mediator and CXCR2 ligand KC led to mobilization of neutrophils from marrow by itself and was augmented 3-fold by low doses of CXCR4-blocking antibody that otherwise had no mobilizing effect. Examination of KC and SDF-1 calcium signaling demonstrated that the effect of KC may, in part, be due to heterologous desensitization to SDF-1. These results suggest that the CXCR4/SDF-1 axis is critical in circulating neutrophil homeostasis and that it may participate in the rapid release of neutrophils from the marrow during inflammation through a novel interaction with inflammatory CXC chemokines. (Blood. 2004;104:565-571)
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Kerfoot, Steven M., Graciela Andonegui, Claudine S. Bonder, and Lixin Liu. "Exogenous stromal cell-derived factor-1 induces modest leukocyte recruitment in vivo." American Journal of Physiology-Heart and Circulatory Physiology 294, no. 6 (June 2008): H2524—H2534. http://dx.doi.org/10.1152/ajpheart.00984.2007.
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Stromal cell-derived factor-1 (SDF-1; CXCL12), a CXC chemokine, has been found to be involved in inflammation models in vivo and in cell adhesion, migration, and chemotaxis in vitro. This study aimed to determine whether exogenous SDF-1 induces leukocyte recruitment in mice. After systemic administration of SDF-1α, expression of the adhesion molecules P-selectin and VCAM-1 in mice was measured using a quantitative dual-radiolabeled Ab assay and leukocyte recruitment in various tissues was evaluated using intravital microscopy. The effect of local SDF-1α on leukocyte recruitment was also determined in cremaster muscle and compared with the effect of the cytokine TNFα and the CXC chemokine keratinocyte-derived chemokine (KC; CXCL1). Systemic administration of SDF-1α (10 μg, 4–5 h) induced upregulation of P-selectin, but not VCAM-1, in most tissues in mice. It caused modest leukocyte recruitment responses in microvasculature of cremaster muscle, intestine, and brain, i.e., an increase in flux of rolling leukocytes in cremaster muscle and intestines, leukocyte adhesion in all three tissues, and emigration in cremaster muscle. Local treatment with SDF-1α (1 μg, 4–5 h) reduced leukocyte rolling velocity and increased leukocyte adhesion and emigration in cremasteric venules, but the responses were much less profound than those elicited by KC or TNFα. SDF-1α-induced recruitment was dependent on endothelial P-selectin, but not P-selectin on platelets. We conclude that the exogenous SDF-1α enhances leukocyte-endothelial cell interactions and induces modest and endothelial P-selectin-dependent leukocyte recruitment.
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Hang, Hardy, Jennifer Bailey, and Carrie Elks. "Oncostatin M Mediates Adipocyte Expression and Secretion of Stromal-Derived Factor 1." Biology 8, no. 1 (March 23, 2019): 19. http://dx.doi.org/10.3390/biology8010019.
Full textAbstract:
Adipose tissue homeostasis depends on interactions between stromal cells, adipocytes, and the cytokines and chemokines they produce. The gp130 cytokine, oncostatin M (OSM), plays a role in adipose tissue homeostasis. Mice, lacking the OSM receptor (OSMR) in adipocytes (OsmrFKO mice), exhibit derangements in adipose tissue, insulin sensitivity, and immune cell balance. Here, we describe a possible role for the chemokine stromal-derived factor 1 (SDF-1) in these alterations. We treated 3T3-L1 adipocytes with OSM and observed a suppression of SDF-1 gene expression and protein secretion, an effect which was partially blunted by OSMR knockdown. However, OsmrFKO mice also exhibited decreased SDF-1 gene and protein expression in adipose tissue. These contrasting results suggest that the loss of adipocyte OSM–OSMR signaling in vivo may be indirectly affecting adipokine production and secretion by altering OSM target genes to ultimately decrease SDF-1 expression in the OsmrFKO mouse. We conclude that adipocyte OSM–OSMR signaling plays a role in adipose tissue SDF-1 production and may mitigate its effects on adipose tissue homeostasis.
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De La Luz Sierra, Maria, Fuquan Yang, Masashi Narazaki, Ombretta Salvucci, David Davis, Robert Yarchoan, Hongwei H. Zhang, Henry Fales, and Giovanna Tosato. "Differential processing of stromal-derived factor-1α and stromal-derived factor-1β explains functional diversity." Blood 103, no. 7 (April 1, 2004): 2452–59. http://dx.doi.org/10.1182/blood-2003-08-2857.
Full textAbstract:
Abstract The chemokine stromal-derived factor-1 (SDF-1), which is constitutively expressed in most tissues as SDF-1α and SDF-1β resulting from alternative gene splicing, regulates hematopoiesis, lymphocyte homing, B-lineage cell growth, and angiogenesis. Because SDF-1α and SDF-1β are constitutively and ubiquitously expressed, their degradation must serve an important regulatory role. Here we show that SDF-1α and SDF-1β are secreted as full-length molecules. When exposed to human serum, full-length SDF-1α (1-68) undergoes processing first at the COOH terminus to produce SDF-1α 1-67 and then at the NH2 terminus to produce SDF-1α 3-67. By contrast, full-length SDF-1β (1-72) is processed only at the NH2 terminus to produce SDF-1β 3-72. CD26/dipeptidyl peptidase is responsible for serum cleavage of SDF-1α and SDF-1β at the NH2 terminus. Serum processing of SDF-1α at the COOH terminus, which has not been previously reported, reduces the ability of the polypeptide to bind to heparin and to cells and to stimulate B-cell proliferation and chemotaxis. The additional processing at the NH2 terminus renders both forms of SDF-1 unable to bind to heparin and to activate cells. The differential processing of SDF-1α and SDF-1β provides biologic significance to the existence of 2 splice forms of the chemokine and adds a tool to precisely regulate SDF-1's biologic activity by changes in specific activity.
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Dwinell, Michael B., Hiroyuki Ogawa, Kim E. Barrett, and Martin F. Kagnoff. "SDF-1/CXCL12 regulates cAMP production and ion transport in intestinal epithelial cells via CXCR4." American Journal of Physiology-Gastrointestinal and Liver Physiology 286, no. 5 (May 2004): G844—G850. http://dx.doi.org/10.1152/ajpgi.00112.2003.
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Human colonic epithelial cells express CXCR4, the sole cognate receptor for the chemokine stromal cell-derived factor (SDF)-1/CXC chemokine ligand (CXCL) 12. The aim of this study was to define the mechanism and functional consequences of signaling intestinal epithelial cells through the CXCR4 chemokine receptor. CXCR4, but not SDF-1/CXCL12, was constitutively expressed by T84, HT-29, HT-29/-18C1, and Caco-2 human colon epithelial cell lines. Studies using T84 cells showed that CXCR4 was G protein-coupled in intestinal epithelial cells. Moreover, stimulation of T84 cells with SDF-1/CXCL12 inhibited cAMP production in response to the adenylyl cyclase activator forskolin, and this inhibition was abrogated by either anti-CXCR4 antibody or receptor desensitization. Studies with pertussis toxin suggested that SDF-1/CXCL12 activated negative regulation of cAMP production through Giα subunits coupled to CXCR4. Consistent with the inhibition of forskolin-stimulated cAMP production, SDF-1/CXCL12 also inhibited forskolin-induced ion transport in voltage-clamped polarized T84 cells. Taken together, these data indicate that epithelial CXCR4 can transduce functional signals in human intestinal epithelial cells that modulate important cAMP-mediated cellular functions.
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van Berkel, Victor, John Barrett, H. Lee Tiffany, Daved H. Fremont, Philip M. Murphy, Grant McFadden, Samuel H. Speck, and Herbert W. Virgin. "Identification of a Gammaherpesvirus Selective Chemokine Binding Protein That Inhibits Chemokine Action." Journal of Virology 74, no. 15 (August 1, 2000): 6741–47. http://dx.doi.org/10.1128/jvi.74.15.6741-6747.2000.
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ABSTRACT Chemokines are involved in recruitment and activation of hematopoietic cells at sites of infection and inflammation. The M3 gene of γHV68, a gamma-2 herpesvirus that infects and establishes a lifelong latent infection and chronic vasculitis in mice, encodes an abundant secreted protein during productive infection. The M3 gene is located in a region of the genome that is transcribed during latency. We report here that the M3 protein is a high-affinity broad-spectrum chemokine scavenger. The M3 protein bound the CC chemokines human regulated upon activation of normal T-cell expressed and secreted (RANTES), murine macrophage inflammatory protein 1α (MIP-1α), and murine monocyte chemoattractant protein 1 (MCP-1), as well as the human CXC chemokine interleukin-8, the murine C chemokine lymphotactin, and the murine CX3C chemokine fractalkine with high affinity (Kd = 1.6 to 18.7 nM). M3 protein chemokine binding was selective, since the protein did not bind seven other CXC chemokines (Kd > 1 μM). Furthermore, the M3 protein abolished calcium signaling in response to murine MIP-1α and murine MCP-1 and not to murine KC or human stromal cell-derived factor 1 (SDF-1), consistent with the binding data. The M3 protein was also capable of blocking the function of human CC and CXC chemokines, indicating the potential for therapeutic applications. Since the M3 protein lacks homology to known chemokines, chemokine receptors, or chemokine binding proteins, these studies suggest a novel herpesvirus mechanism of immune evasion.
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Manferdini, Cristina, Yasmin Saleh, Paolo Dolzani, Elena Gabusi, Diego Trucco, Giuseppe Filardo, and Gina Lisignoli. "Impact of Isolation Procedures on the Development of a Preclinical Synovial Fibroblasts/Macrophages in an In Vitro Model of Osteoarthritis." Biology 9, no. 12 (December 10, 2020): 459. http://dx.doi.org/10.3390/biology9120459.
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There is a lack ofin vitromodels able to properly represent osteoarthritis (OA) synovial tissue (ST). We aimed to characterize OA ST and to investigate whether a mechanical or enzymatic digestion procedures influence synovial cell functional heterogeneity in vitro. Procedures using mechanical nondigested fragments (NDF), synovial digested fragments (SDF), and filtrated synovial digested cells (SDC) were compared. An immunophenotypic profile was performed to distinguish synovial fibroblasts (CD55, CD73, CD90, CD106), macrophages (CD14, CD68), M1-like (CD80, CD86), and M2-like (CD163, CD206) synovial macrophages. Pro-inflammatory (interleukin 6 IL6), tumor necrosis factor alpha (TNFα), chemokine C-C motif ligand 3 (CCL3/MIP1α), C-X- motif chemokine ligand 10 (CXCL10/IP10) and anti-inflammatory (interleukin 10 (IL10)), transforming growth factor beta 1 (TGFβ1), C-C motif chemokine ligand 18 (CCL18) cytokines were evaluated. CD68 and CD163 markers were higher in NDF and SDF compared to the SDC procedure, while CD80, CD86, and CD206 were higher only in NDF compared to the SDC procedure. Synovial fibroblast markers showed similar percentages. TNFα, CCL3/MIP1α, CXCL10/IP10, and CCL18 were higher in NDF compared to SDC, but not compared to SDF. IL10 and TGFβ1 were higher in NDF than SDC at the molecular level, while IL6 did not show differences among procedures. We demonstrated that NDF isolation procedures better preserved the heterogeneity of specific OA synovial populations (fibroblasts, macrophages), fostering their use for testing new cell therapies or drugs for OA, reducing or avoiding the use of animal models.
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Hodohara, Keiko, Nobutaka Fujii, Naoki Yamamoto, and Kenneth Kaushansky. "Stromal cell-derived factor-1 (SDF-1) acts together with thrombopoietin to enhance the development of megakaryocytic progenitor cells (CFU-MK)." Blood 95, no. 3 (February 1, 2000): 769–75. http://dx.doi.org/10.1182/blood.v95.3.769.003a49_769_775.
Full textAbstract:
Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine that acts as a stimulator of pre-B lymphocyte cell growth and as a chemoattractant for T cells, monocytes, and hematopoietic stem cells. More recent studies also suggest that megakaryocytes migrate in response to SDF-1. Because genetic elimination of SDF-1 or its receptor lead to marrow aplasia, we investigated the effect of SDF-1 on megakaryocyte progenitors (colony-forming units-megakaryocyte [CFU-MK]). We report that SDF-1 augments the growth of CFU-MK from whole murine bone marrow cells when combined with thrombopoietin (TPO). The addition of SDF-1 to interleukin-3 (IL-3) or stem cell factor (SCF) had no effect. Specific antagonists for CXCR4 (the sole receptor for SDF-1), T22, and 1-9 (P2G) SDF-1 reduced megakaryocyte colony growth induced by TPO alone, suggesting that many culture systems contain endogenous levels of the chemokine that contributes to the TPO effect. To examine whether SDF-1 has direct effects on CFU-MK, we developed a new protocol to purify megakaryocyte progenitors. CFU-MK were highly enriched in CD41high c-kithigh cells generated from lineage-depleted TPO-primed marrow cells. Because the growth-promoting effects of SDF-1 were also observed when highly purified populations of CFU-MK were tested in serum-free cultures, these results suggest that SDF-1 directly promotes the proliferation of megakaryocytic progenitors in the presence of TPO, and in this way contributes to the favorable effects of the bone marrow microenvironment on megakaryocyte development.
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Ma, Qing, Dan Jones, Paul R. Borghesani, Rosalind A. Segal, Takashi Nagasawa, Tadamitsu Kishimoto, Roderick T. Bronson, and Timothy A. Springer. "Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice." Proceedings of the National Academy of Sciences 95, no. 16 (August 4, 1998): 9448–53. http://dx.doi.org/10.1073/pnas.95.16.9448.
Full textAbstract:
The chemokine stromal cell-derived factor 1, SDF-1, is an important regulator of leukocyte and hematopoietic precursor migration and pre-B cell proliferation. The receptor for SDF-1, CXCR4, also functions as a coreceptor for T-tropic HIV-1 entry. We find that mice deficient for CXCR4 die perinatally and display profound defects in the hematopoietic and nervous systems. CXCR4-deficient mice have severely reduced B-lymphopoiesis, reduced myelopoiesis in fetal liver, and a virtual absence of myelopoiesis in bone marrow. However, T-lymphopoiesis is unaffected. Furthermore, the cerebellum develops abnormally with an irregular external granule cell layer, ectopically located Purkinje cells, and numerous chromophilic cell clumps of abnormally migrated granule cells within the cerebellar anlage. Identical defects are observed in mice lacking SDF-1, suggesting a monogamous relationship between CXCR4 and SDF-1. This receptor-ligand selectivity is unusual among chemokines and their receptors, as is the function in migration of nonhematopoietic cells.
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Yang, Otto O., Stephen L. Swanberg, Zhijian Lu, Michelle Dziejman, John McCoy, Andrew D. Luster, Bruce D. Walker, and Steven H. Herrmann. "Enhanced Inhibition of Human Immunodeficiency Virus Type 1 by Met-Stromal-Derived Factor 1β Correlates with Down-Modulation of CXCR4." Journal of Virology 73, no. 6 (June 1, 1999): 4582–89. http://dx.doi.org/10.1128/jvi.73.6.4582-4589.1999.
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ABSTRACT CXCR4 is a chemokine receptor used by some strains of HIV-1 as an entry coreceptor in association with cell surface CD4 on human cells. In human immunodeficiency virus type 1 (HIV-1)-infected individuals, the appearance of viral isolates with a tropism for CXCR4 (T tropic) has been correlated with late disease progression. The presumed natural ligands for CXCR4 are SDF-1α and SDF-1β, which are proposed to play a role in blocking T-tropic HIV-1 cell entry. Here, we demonstrate that addition of an N-terminal methionine residue to SDF-1β (Met-SDF-1β) results in a dramatically enhanced functional activity compared to that of native SDF-1β. Equivalent concentrations of Met-SDF-1β are markedly more inhibitory for T-tropic HIV-1 replication than SDF-1β. A comparison of the biological activities of these two forms of SDF-1β reveals that Met-SDF-1β induces a more pronounced intracellular calcium flux yet binds with slightly lower affinity to CXCR4 than SDF-1β. Down-modulation of CXCR4 is similar after exposure of cells to either chemokine form for 2 h. However, after a 48-h incubation, the surface expression of CXCR4 is much lower for cells treated with Met-SDF-1β. The enhanced blocking of T-tropic HIV-1 by Met-SDF-1β appears to be related to prolonged CXCR4 down-modulation.
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Ayehunie, Seyoum, Eduardo A. Garcia-Zepeda, James A. Hoxie, Richard Horuk, Thomas S. Kupper, Andrew D. Luster, and Ruth M. Ruprecht. "Human Immunodeficiency Virus-1 Entry Into Purified Blood Dendritic Cells Through CC and CXC Chemokine Coreceptors." Blood 90, no. 4 (August 15, 1997): 1379–86. http://dx.doi.org/10.1182/blood.v90.4.1379.
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Abstract Blood dendritic cells (DC) are susceptible to both macrophage (M) and T-cell line (T) tropic human immunodeficiency virus type 1. The CC chemokines RANTES, macrophage inflammatory protein-1α (MIP-1α), MIP-1β, eotaxin, and, to a lesser extent, monocyte chemoattractant protein-1 (MCP-1) and MCP-4 blocked entry of M-tropic virus into blood DC. The CXC chemokine, SDF-1, a fusin (CXCR4 chemokine receptor) ligand, and an antifusin antibody inhibited DC entry by T-tropic virus. Purified blood DC contained CCR1, CCR2, CCR3, and CCR5 as well as the CXCR4 chemokine receptor RNA transcripts and high levels of fusin on the cell surface. The coexpression of multiple chemokine receptors offers a molecular mechanism to explain the permissiveness of DC for both M- and T-tropic viruses.
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Ayehunie, Seyoum, Eduardo A. Garcia-Zepeda, James A. Hoxie, Richard Horuk, Thomas S. Kupper, Andrew D. Luster, and Ruth M. Ruprecht. "Human Immunodeficiency Virus-1 Entry Into Purified Blood Dendritic Cells Through CC and CXC Chemokine Coreceptors." Blood 90, no. 4 (August 15, 1997): 1379–86. http://dx.doi.org/10.1182/blood.v90.4.1379.1379_1379_1386.
Full textAbstract:
Blood dendritic cells (DC) are susceptible to both macrophage (M) and T-cell line (T) tropic human immunodeficiency virus type 1. The CC chemokines RANTES, macrophage inflammatory protein-1α (MIP-1α), MIP-1β, eotaxin, and, to a lesser extent, monocyte chemoattractant protein-1 (MCP-1) and MCP-4 blocked entry of M-tropic virus into blood DC. The CXC chemokine, SDF-1, a fusin (CXCR4 chemokine receptor) ligand, and an antifusin antibody inhibited DC entry by T-tropic virus. Purified blood DC contained CCR1, CCR2, CCR3, and CCR5 as well as the CXCR4 chemokine receptor RNA transcripts and high levels of fusin on the cell surface. The coexpression of multiple chemokine receptors offers a molecular mechanism to explain the permissiveness of DC for both M- and T-tropic viruses.
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Choi, Won-Tak, Shaomin Tian, Chang-Zhi Dong, Santosh Kumar, Dongxiang Liu, Navid Madani, Jing An, Joseph G. Sodroski, and Ziwei Huang. "Unique Ligand Binding Sites on CXCR4 Probed by a Chemical Biology Approach: Implications for the Design of Selective Human Immunodeficiency Virus Type 1 Inhibitors." Journal of Virology 79, no. 24 (December 15, 2005): 15398–404. http://dx.doi.org/10.1128/jvi.79.24.15398-15404.2005.
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ABSTRACT The chemokine receptor CXCR4 plays an important role as the receptor for the normal physiological function of stromal cell-derived factor 1α (SDF-1α) and the coreceptor for the entry of human immunodeficiency virus type 1 (HIV-1) into the cell. In a recent work (S. Tian et al., J. Virol. 79:12667-12673, 2005), we found that many residues throughout CXCR4 transmembrane (TM) and extracellular loop 2 domains are specifically involved in interaction with HIV-1 gp120, as most of these sites did not play a role in either SDF-1α binding or signaling. These results provided direct experimental evidence for the distinct functional sites on CXCR4 for HIV-1 and the normal ligand SDF-1α. To further understand the CXCR4-ligand interaction and to develop new CXCR4 inhibitors to block HIV-1 entry, we have recently generated a new family of unnatural chemokines, termed synthetically and modularly modified (SMM) chemokines, derived from the native sequence of SDF-1α or viral macrophage inflammatory protein II (vMIP-II). These SMM chemokines contain various de novo-designed sequence replacements and substitutions by d-amino acids and display more enhanced CXCR4 selectivity, binding affinities, and/or anti-HIV activities than natural chemokines. Using these novel CXCR4-targeting SMM chemokines as receptor probes, we conducted ligand binding site mapping experiments on a panel of site-directed mutants of CXCR4. Here, we provide the first experimental evidence demonstrating that SMM chemokines interact with many residues on CXCR4 TM and extracellular domains that are important for HIV-1 entry, but not SDF-1α binding or signaling. The preferential overlapping in the CXCR4 binding residues of SMM chemokines with HIV-1 over SDF-1α illustrates a mechanism for the potent HIV-1 inhibition by these SMM chemokines. The discovery of distinct functional sites or conformational states influenced by these receptor sites mediating different functions of the natural ligand versus the viral or synthetic ligands has important implications for drug discovery, since the sites shared by SMM chemokines and HIV-1 but not by SDF-1α can be targeted for the development of selective HIV-1 inhibitors devoid of interference with normal SDF-1α function.
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Veldkamp, Christopher T., Joshua J. Ziarek, Jidong Su, Harihar Basnet, Richard Lennertz, Joshua J. Weiner, Francis C. Peterson, John E. Baker, and Brian F. Volkman. "Monomeric structure of the cardioprotective chemokine SDF-1/CXCL12." Protein Science 18, no. 7 (May 20, 2009): 1359–69. http://dx.doi.org/10.1002/pro.167.
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Ngo, Hai, Evdoxia Hatjiharissi, Xavier Leleu, Judith Runnels, Anne-Sophie Moreau, Xiaoying Jia, Garrett O’Sullivan, et al. "The CXCR4/SDF-1 Axis Regulates Migration and Adhesion in Waldenstrom Macroglobulinemia." Blood 108, no. 11 (November 1, 2006): 2418. http://dx.doi.org/10.1182/blood.v108.11.2418.2418.
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Abstract Background: Waldenstrom Macroglobulinemia (WM) is characterized by widespread involvement of the bone marrow (BM), and lymphadenopathy in 20% of the patients, implying continuous trafficking of WM cells into and out of the BM and lymph nodes. The normal process of B-cell homing is regulated by cytokines, chemokines, and adhesion molecules. One of the most extensively studied chemokines in migration is stromal derived factor SDF-1 and its receptor CXCR4. Here we study the role of chemokine receptors, and the SDF-1/CXCR4 axis on migration and adhesion in WM. Methods: Flow cytometry for CXC and CC chemokine receptors (CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CCR2, CCR4, CCR5, CCR6 and CCR7), and adhesion molecules (VLA-4 and LFA-1) on WM cell lines (BCWM.1 and WM-WSU) and patient samples was performed. Migration was determined using the transwell migration assay (Costar, NY). Cells were placed in the upper chambers of the migration assay with 1% FCS medium in the presence of serial concentrations of SDF-1 in the lower chambers. After 4 hours of incubation, cells that migrated to the lower chambers were counted. Similarly, adhesion was determined using an adhesion assay (EMD Biosciences, San Diego, CA) with 96-well plated coated with fibronectin. Immunoblotting for proteins downstream of CXCR4 was performed. The CXCR4 inhibitor AMD3100 (10–100uM, Sigma, MO) and Gi protein inhibitor pertussis toxin PTX (10–200ng/ml, Sigma, MO) were used to inhibit CXCR4 signaling. Results: The following chemokine receptors were expressed on patient CD19+WM cells with over 30% expression: CXCR1 (mean 60%), CXCR2 (mean 47%), CXCR4 (mean 47%), CXCR5 (mean 69%), CCR4 (mean 54%) and CCR6 (mean 61%). Similar expression was observed on WM cell lines. We next determined the effect of SDF-1 on migration and signaling pathways in WM. SDF-1 (10–100nM) induced migration in a bell-shaped curve with 30nM inducing maximum migration (110% compared to control). SDF-1 30nM induced a rapid activation of signaling pathways downstream of CXCR4 including pERK1/2, pAKT, and pPKC at 1 min, with maximum activation at 5min. The CXCR4 inhibitor AMD3100 inhibited migration of BCWM.1 in the presence of 30nM SDF-1, with AMD3100 10uM inhibiting migration at 59% of control, and 20 to 50uM leading to a plateau in inhibition of migration at 54% of control. AMD3100 inhibited pERK and pPKC activation, downstream of CXCR4 in a dose-dependent fashion. Similar results were observed using PTX, with inhibition of migration of WM cells at 50% compared to control. To determine the role of SDF-1 on adhesion, we first demonstrated that WM cells from patients and cell lines expressed high levels of surface VLA-4 expression (mean 95% surface expression). WM cells had an increase in adhesion to fibronectin (VLA-4 ligand) compared to BSA control. AMD3100 10uM inhibited adhesion to fibronectin (63 % of control), indicating that the SDF-1/CXCR4 axis regulates adhesion. Conclusion: CXCR4 is highly expressed on WM cells and regulates migration and adhesion, indicating a potential role in regulating WM trafficking into the BM and lymph nodes. These studies provide the preclinical framework to study CXCR4 inhibitors in the regulation of homing and adhesion in WM.
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Proost, Paul, Patricia Menten, Sofie Struyf, Evemie Schutyser, Ingrid De Meester, and Jo Van Damme. "Cleavage by CD26/dipeptidyl peptidase IV converts the chemokine LD78β into a most efficient monocyte attractant and CCR1 agonist." Blood 96, no. 5 (September 1, 2000): 1674–80. http://dx.doi.org/10.1182/blood.v96.5.1674.
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Abstract Chemokines are proinflammatory cytokines that play a role in leukocyte migration and activation. Recent reports showed that RANTES (regulated on activation normal T-cell expressed and secreted chemokine), eotaxin, macrophage-derived chemokine (MDC), and stromal cell–derived factor-1 (SDF-1) are NH2-terminally truncated by the lymphocyte surface glycoprotein and protease CD26/dipeptidyl peptidase IV (CD26/DPP IV). Removal of the NH2-terminal dipeptide resulted in impaired inflammatory properties of RANTES, eotaxin, MDC, and SDF-1. The potential CD26/DPP IV substrate macrophage inflammatory protein–1β (MIP-1β) and the related chemokine, LD78α (ie, one of the MIP-1α isoforms), were not affected by this protease. However, CD26/DPP IV cleaved LD78β, a most potent CCR5 binding chemokine and inhibitor of macrophage tropic human immunodeficiency virus–1 (HIV-1) infection, into LD78β(3-70). Naturally truncated LD78β(3-70), but not truncated MIP-1β, was recovered as an abundant chemokine form from peripheral blood mononuclear cells. In contrast to all other chemokines processed by CD26/DPP IV, LD78β(3-70) had increased chemotactic activity in comparison to intact LD78β. With a minimal effective concentration of 30 pmol/L, LD78β(3-70) became the most efficient monocyte chemoattractant. LD78β(3-70) retained its high capacity to induce an intracellular calcium increase in CCR5-transfected cells. Moreover, on CCR1 transfectants, truncated LD78β(3-70) was 30-fold more potent than intact LD78β. Thus, CD26/DPP IV can exert not only a negative but also a positive feedback during inflammation by increasing the specific activity of LD78β. CD26/DPP IV–cleaved LD78β(3-70) is the most potent CCR1 and CCR5 agonist that retains strong anti–HIV-1 activity, indicating the importance of the chemokine-protease interaction in normal and pathologic conditions.
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Proost, Paul, Patricia Menten, Sofie Struyf, Evemie Schutyser, Ingrid De Meester, and Jo Van Damme. "Cleavage by CD26/dipeptidyl peptidase IV converts the chemokine LD78β into a most efficient monocyte attractant and CCR1 agonist." Blood 96, no. 5 (September 1, 2000): 1674–80. http://dx.doi.org/10.1182/blood.v96.5.1674.h8001674a_1674_1680.
Full textAbstract:
Chemokines are proinflammatory cytokines that play a role in leukocyte migration and activation. Recent reports showed that RANTES (regulated on activation normal T-cell expressed and secreted chemokine), eotaxin, macrophage-derived chemokine (MDC), and stromal cell–derived factor-1 (SDF-1) are NH2-terminally truncated by the lymphocyte surface glycoprotein and protease CD26/dipeptidyl peptidase IV (CD26/DPP IV). Removal of the NH2-terminal dipeptide resulted in impaired inflammatory properties of RANTES, eotaxin, MDC, and SDF-1. The potential CD26/DPP IV substrate macrophage inflammatory protein–1β (MIP-1β) and the related chemokine, LD78α (ie, one of the MIP-1α isoforms), were not affected by this protease. However, CD26/DPP IV cleaved LD78β, a most potent CCR5 binding chemokine and inhibitor of macrophage tropic human immunodeficiency virus–1 (HIV-1) infection, into LD78β(3-70). Naturally truncated LD78β(3-70), but not truncated MIP-1β, was recovered as an abundant chemokine form from peripheral blood mononuclear cells. In contrast to all other chemokines processed by CD26/DPP IV, LD78β(3-70) had increased chemotactic activity in comparison to intact LD78β. With a minimal effective concentration of 30 pmol/L, LD78β(3-70) became the most efficient monocyte chemoattractant. LD78β(3-70) retained its high capacity to induce an intracellular calcium increase in CCR5-transfected cells. Moreover, on CCR1 transfectants, truncated LD78β(3-70) was 30-fold more potent than intact LD78β. Thus, CD26/DPP IV can exert not only a negative but also a positive feedback during inflammation by increasing the specific activity of LD78β. CD26/DPP IV–cleaved LD78β(3-70) is the most potent CCR1 and CCR5 agonist that retains strong anti–HIV-1 activity, indicating the importance of the chemokine-protease interaction in normal and pathologic conditions.
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Doranz, Benjamin J., Michael J. Orsini, Julie D. Turner, Trevor L. Hoffman, Joanne F. Berson, James A. Hoxie, Stephen C. Peiper, Lawrence F. Brass, and Robert W. Doms. "Identification of CXCR4 Domains That Support Coreceptor and Chemokine Receptor Functions." Journal of Virology 73, no. 4 (April 1, 1999): 2752–61. http://dx.doi.org/10.1128/jvi.73.4.2752-2761.1999.
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ABSTRACT The interaction of the chemokine stromal cell-derived factor 1 (SDF-1) with its receptor CXCR4 is vital for cell trafficking during development, is capable of inhibiting human immunodeficiency virus type 1 (HIV-1) utilization of CXCR4 as a coreceptor, and has been implicated in delaying disease progression to AIDS in vivo. Because of the importance of this chemokine-chemokine receptor pair to both development and disease, we investigated the molecular basis of the interaction between CXCR4 and its ligands SDF-1 and HIV-1 envelope. Using CXCR4 chimeras and mutants, we determined that SDF-1 requires the CXCR4 amino terminus for binding and activates downstream signaling pathways by interacting with the second extracellular loop of CXCR4. SDF-1-mediated activation of CXCR4 required the Asp-Arg-Tyr motif in the second intracellular loop of CXCR4, was pertussis toxin sensitive, and did not require the distal C-terminal tail of CXCR4. Several CXCR4 mutants that were not capable of binding SDF-1 or signaling still supported HIV-1 infection, indicating that the ability of CXCR4 to function as a coreceptor is independent of its ability to signal. Direct binding studies using the X4 gp120s HXB, BH8, and MN demonstrated the ability of HIV-1 gp120 to bind directly and specifically to the chemokine receptor CXCR4 in a CD4-dependent manner, using a conformationally complex structure on CXCR4. Several CXCR4 variants that did not support binding of soluble gp120 could still function as viral coreceptors, indicating that detectable binding of monomeric gp120 is not always predictive of coreceptor function.
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Braunersreuther, Vincent, François Mach, and Sabine Steffens. "The specific role of chemokines in atherosclerosis." Thrombosis and Haemostasis 97, no. 05 (2007): 714–21. http://dx.doi.org/10.1160/th07-01-0036.
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SummaryAtherosclerosis is a chronic inflammatory disease that represents the primary cause of heart disease and stroke.The recruitment of inflammatory cells in the intima is an essential step in the development and progression of atherosclerosis.This process is triggered by local production of chemokines and chemokine receptors from activated endothelial cells and inflammatory cells. Various members of the CC chemokine family (e.g. MCP- 1/CCL2) as well as CXC family (e.g. IL-8/CCL8, IP-10/CXCL10, SDF-1/CXCL12) and, more recently, fractalkine/CX3CL1 have been implicated in atherosclerosis development. Latest findings in animal models suggest that blocking chemokine/chemokine receptor interactions may serve as a suitable approach to treat atherosclerosis. Likewise, chemokine antagonists that inhibit leukocyte recruitment could particularly be interesting to treat inflammation in response to myocardial infarction, the major consequence of atherosclerosis.
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Burns, Jennifer M., Bretton C. Summers, Yu Wang, Anita Melikian, Rob Berahovich, Zhenhua Miao, Mark E. T. Penfold, et al. "A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development." Journal of Experimental Medicine 203, no. 9 (August 28, 2006): 2201–13. http://dx.doi.org/10.1084/jem.20052144.
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The chemokine stromal cell–derived factor (SDF-1; also known as chemokine ligand 12 [CXCL12]) regulates many essential biological processes, including cardiac and neuronal development, stem cell motility, neovascularization, angiogenesis, apoptosis, and tumorigenesis. It is generally believed that SDF-1 mediates these many disparate processes via a single cell surface receptor known as chemokine receptor 4 (CXCR4). This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell α chemoattractant (I-TAC; also known as CXCL11). Membrane-associated CXCR7 is expressed on many tumor cell lines, on activated endothelial cells, and on fetal liver cells, but on few other cell types. Unlike many other chemokine receptors, ligand activation of CXCR7 does not cause Ca2+ mobilization or cell migration. However, expression of CXCR7 provides cells with a growth and survival advantage and increased adhesion properties. Consistent with a role for CXCR7 in cell survival and adhesion, a specific, high affinity small molecule antagonist to CXCR7 impedes in vivo tumor growth in animal models, validating this new receptor as a target for development of novel cancer therapeutics.
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Hupe, Marie C., Miguel Gosalbez, Soum D. Lokeshwar, John Shields, Travis J. Yates, and Vinata B. Lokeshwar. "Clinical significance of SDF-1 isoforms in bladder cancer." Journal of Clinical Oncology 33, no. 7_suppl (March 1, 2015): 334. http://dx.doi.org/10.1200/jco.2015.33.7_suppl.334.
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334 Background: Stroma-Derived Factor (SDF)-1 is a ligand for chemokine receptors CXCR4 and CXCR7. The six known SDF-1 isoforms are generated by alternative mRNA splicing. While SDF-1 expression has been detected in various malignancies, only a few studies have reported differential expression of SDF-1 isoforms and its clinical significance. In this study we evaluated the expression three SDF-1 isoforms (α,β,γ) in bladder cancer (BCa). Methods: Using quantitative PCR, mRNA levels of SDF-1α, SDF-1β and SDF-1γ were measured in bladder tissues (normal: 25; BCa: 44) and urine specimens (n=210; normal: 28; benign conditions: 74; BCa: 57, history of BCa (HxBCa): 35, Hx other Ca: 8; other Ca: 8) from consecutive patients. The transcript levels were normalized to β-actin. Correlation between SDF1-isoform transcript levels and clinical outcome (metastasis and disease specific mortality (DSM)) was evaluated in univariate and multivariate analyses. Results: Among SDF-1 isoforms, only SDF-1β mRNA was significantly overexpressed by 2.5-6-fold in BCa tissues when compared to normal bladder tissues. While SDF-1α was expressed in bladder tissues, SDF-1γ expression was undetectable. In univariate analysis, pathologic stage, lymph node positivity for tumor, SDF-1α and SDF-1β transcript levels significantly associated with metastasis and DSM. However, in multivariate analysis, stage (P=0.005) and SDF-1β levels (P=0.017) were independent predictors of metastasis and DSM. In exfoliated urothelial cells, only SDF-1β mRNA levels were differentially expressed and having 91.2% sensitivity and 73.8% specificity for detecting BCa. In patients with HxBCa, elevated SDF-1β levels indicated 4.3-fold increased risk (chi-square: 15.1; P=0.0001; relative risk = 4.3) for developing recurrence within 6-months. Conclusions: SDF-1 isoforms are differentially expressed in bladder tissues and exfoliated urothelial cells. SDF-1β mRNA levels in BCa tissues predict poor prognosis. Further, SDF-1β mRNA levels in exfoliated cells detect BCa with high sensitivity and are potential predictors of future recurrence. Support: Grant NCI/NIH R01 CA-72821-14; Women’s Cancer Association – University of Miami.
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Liepelt, Anke, and Frank Tacke. "Stromal cell-derived factor-1 (SDF-1) as a target in liver diseases." American Journal of Physiology-Gastrointestinal and Liver Physiology 311, no. 2 (August 1, 2016): G203—G209. http://dx.doi.org/10.1152/ajpgi.00193.2016.
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The chemokine stromal cell-derived factor-1 (SDF-1) or CXCL12 is constitutively expressed in healthy liver. However, its expression increases following acute or chronic liver injury. Liver sinusoidal endothelial cells (LSEC), hepatic stellate cells (HSC), and malignant hepatocytes are important sources of SDF-1/CXCL12 in liver diseases. CXCL12 is able to activate two chemokine receptors with different downstream signaling pathways, CXCR4 and CXCR7. CXCR7 expression is relevant on LSEC, while HSC, mesenchymal stem cells, and tumor cells mainly respond via CXCR4. Here, we summarize recent developments in the field of liver diseases involving this chemokine and its receptors. SDF-1-dependent signaling contributes to modulating acute liver injury and subsequent tissue regeneration. By activating HSC and recruiting mesenchymal cells from bone marrow, CXCL12 can promote liver fibrosis progression, while CXCL12-CXCR7 interactions endorse proregenerative responses in chronic injury. Moreover, the SDF-1 pathway is linked to development of hepatocellular carcinoma (HCC) by promoting tumor growth, angiogenesis, and HCC metastasis. High hepatic CXCR4 expression has been suggested as a biomarker indicating poor prognosis of HCC patients. Tumor-infiltrating myeloid-derived suppressor cells (MDSC) also express CXCR4 and migrate toward CXCL12. Thus CXCL12 inhibition might not only directly block HCC growth but also modulate the tumor microenvironment (angiogenesis, MDSC), thereby sensitizing HCC patients to conventional or emerging novel cancer therapies (e.g., sorafenib, regorafenib, nivolumab, pembrolizumab). We herein summarize the current knowledge on the complex interplay between CXCL12 and CXCR4/CXCR7 in liver diseases and discuss approaches on the therapeutic targeting of these axes in hepatitis, fibrosis, and liver cancer.
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Wang, JiangFang, Susanne Marschner, and Terri H. Finkel. "CXCR4 engagement is required for HIV-1–induced L-selectin shedding." Blood 103, no. 4 (February 15, 2004): 1218–21. http://dx.doi.org/10.1182/blood-2003-02-0576.
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Abstract The chemokine receptor, CXCR4, serves as the primary coreceptor for entry of T-cell tropic human immunodeficiency virus (HIV). Binding of either the CXC-chemokine, stromal-derived factor 1α (SDF-1α), or a CXCR4 antagonist, AMD3100, to CXCR4 inhibits infection of CD4+ T cells by T-tropic HIV-1, although only SDF-1α triggers T-cell signaling cascades. We have previously demonstrated that ligation of CD4 by T-cell tropic HIV-1 NL4-3 induces metalloproteinase-dependent L-selectin (CD62L) shedding on resting CD4+ T cells. However, the role of CXCR4 in HIV-induced L-selectin shedding is unclear. Here, we show that L-selectin shedding induced by HIV-1 NL4-3 is completely reversed by AMD3100, but not SDF-1α, although SDF-1α alone does not induce L-selectin shedding. These results indicate that engagement of both CD4 and CXCR4 is required for HIV-induced shedding of L-selectin on primary resting CD4+ T cells.
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Ghobrial, Irene M., Mona Melhem, Ujjal Singha, Diane George, Michael Timm, Lanie Francis, Yazan Alsayed, et al. "Role of the Chemokine Receptor CXCR4 in Waldenstrom Macroglobulinemia." Blood 106, no. 11 (November 16, 2005): 993. http://dx.doi.org/10.1182/blood.v106.11.993.993.
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Abstract Waldenstrom Macroglobulinemia (WM) is characterized by the presence of lymphoplasmacytic cells in the bone marrow, and often in the lymph nodes. The mechanisms by which cells migrate/home to the bone marrow are poorly understood. The chemokine receptor CXCR4 and its ligand SDF-1 have been implicated in the migration and homing of lymphocytes. The objective of this study was to begin to identify the role of CXCR4 in WM. Paraffin embedded tissues were obtained after informed consent from 10 bone marrow samples of asymptomatic WM/monoclonal gammopathy of undetermined significance (MGUS) (n=5) and symptomatic WM (n=5). Four normal bone marrow samples were obtained for control. CXCR4 expression was determined using anti-CXCR4 antibody (Affinity Bioreagents, Golden, CO) 1:200 dilution for 16hrs, and a scale of 0–3+ was used to determine relative expression in the lymphocytes. Anti-CD20 antibody was used to determine the presence of lymphocytes in the samples. To determine whether the receptor is functional, migration was performed with the WM cell line (WSU-WM, kind gift from Dr. Al-Khatib, Wayne State University) and using a transwell migration assay (Costar, Corning, NY) with serial dilutions of SDF-1 (10-100nM). Comparison between the asymptomatic and symptomatic WM groups was performed by c2 test, and Mann-Whitney test, as appropriate. The baseline patient characteristics are displayed in table 1. CXCR4 expression was present on the surface of scattered lymphocytes in the normal bone marrow (median expression 1+). The expression of CXCR4 was increased in the asymptomatic/MGUS cases of WM (median expression 2+). In contrast, CXCR4 expression was downregulated in 4/5 cases of symptomatic WM specifically all the ones with extensive involvement of the bone marrow with lymphoplasmacytic cells (median expression 0). SDF-1 induced a bell- shaped response of migration in the WM cells with the maximal migration occurring at 1-10nM SDF-1. SDF-1 1-10nM induced 340% increase in migration as compared to untreated cells. However, high doses of SDF-1 100nM did not induce any migration as compared to untreated cells indicating inhibition of migration in response to high doses of SDF-1. In summary, we demonstrate that the CXCR4 receptor is functional and induces migration indicating that it plays a role in the migration of WM cells to the bone marrow. In addition, we demonstrate that CXCR4 expression is downregulated in WM with high infiltration of cells in the bone marrow as compared to those with minimal infiltration. These results may be due to the high level of SDF-1 in the bone marrow that induce downregulation of CXCR4. High levels of SDF-1 may downregulate the receptor and inhibit migration in order to confine the cells within the bone marrow. Supported in part by an ASH scholar award and the RFW. Patient characteristics Asymptomatic WM/MGUS, (range), (N=5) Symptomatic WM, (range) (N=5) Median age at diagnosis 67.6 (55.8–78) 71.5 (61–77) Median IgM level (mg/dL) 997 (904–1490) 5410 (2000–7820) Median Hb (gm/dL) 12.6 (11.1–15.1) 10.8 (9.3–11.6) Organomegaly (liver or spleen) N 20% Lymphadenopathy N 40% Median involvement of tumor cells in the BM in % 5% 30(10–60)
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de Gorter, David J. J., Rogier M. Reijmers, Esther A. Beuling, Hildegonda P. H. Naber, Annemieke Kuil, Marie José Kersten, Steven T. Pals, and Marcel Spaargaren. "The small GTPase Ral mediates SDF-1–induced migration of B cells and multiple myeloma cells." Blood 111, no. 7 (April 1, 2008): 3364–72. http://dx.doi.org/10.1182/blood-2007-08-106583.
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Abstract Chemokine-controlled migration plays a critical role in B-cell development, differentiation, and function, as well as in the pathogenesis of B-cell malignancies, including the plasma cell neoplasm multiple myeloma (MM). Here, we demonstrate that stimulation of B cells and MM cells with the chemokine stromal cell–derived factor-1 (SDF-1) induces strong migration and activation of the Ras-like GTPase Ral. Inhibition of Ral, by expression of the dominant negative RalN28 mutant or of RalBPΔGAP, a Ral effector mutant that sequesters active Ral, results in impaired SDF-1–induced migration of B cells and MM cells. Of the 2 Ral isoforms, RalA and RalB, RalB was found to mediate SDF-1–induced migration. We have recently shown that Btk, PLCγ2, and Lyn/Syk mediate SDF-1–controlled B-cell migration; however, SDF-1–induced Ral activation is not affected in B cells deficient in these proteins. In addition, treatment with pharmacological inhibitors against PI3K and PLC or expression of dominant-negative Ras did not impair SDF-1–induced Ral activation. Taken together, these results reveal a novel function for Ral, that is, regulation of SDF-1–induced migration of B cells and MM cells, thereby providing new insights into the control of B-cell homeostasis, trafficking, and function, as well as into the pathogenesis of MM.
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Hosie, Margaret J., Nelleke Broere, Joseph Hesselgesser, Julie D. Turner, James A. Hoxie, James C. Neil, and Brian J. Willett. "Modulation of Feline Immunodeficiency Virus Infection by Stromal Cell-Derived Factor." Journal of Virology 72, no. 3 (March 1, 1998): 2097–104. http://dx.doi.org/10.1128/jvi.72.3.2097-2104.1998.
Full textAbstract:
ABSTRACT The α-chemokine receptor CXCR4 has recently been shown to support syncytium formation mediated by strains of feline immunodeficiency virus (FIV) that have been selected for growth in the Crandell feline kidney cell line (CrFK-tropic virus). Given that both human and feline CXCR4 support syncytium formation mediated by FIV, we investigated whether human stromal cell-derived factor (SDF-1) would inhibit infection with FIV. Human SDF-1α and SDF-1β bound with a high affinity (KD s of 12.0 and 10.4 nM, respectively) to human cells stably expressing feline CXCR4, and treatment of CrFK cells with human SDF-1α resulted in a dose-dependent inhibition of infection by FIVPET. No inhibitory activity was detected when the interleukin-2 (IL-2)-dependent feline T-cell line Mya-1 was used in place of CrFK cells, suggesting the existence of a CXCR4-independent mechanism of infection. Furthermore, neither the human β-chemokines RANTES, MIP-1α, MIP-1β, and MCP-1 nor the α-chemokine IL-8 had an effect on infection of either CrFK or Mya-1 cells with CrFK-tropic virus. Envelope glycoprotein purified from CrFK-tropic virus competed specifically for binding of SDF-1α to feline CXCR4 and CXCR4 expression was reduced in FIV-infected cells, suggesting that the inhibitory activity of SDF-1α in CrFK cells may be the result of steric hindrance of the virus-receptor interaction following the interaction between SDF and CXCR4. Prolonged incubation of CrFK cells with SDF-1α led to an enhancement rather than an inhibition of infection. Flow cytometric analysis revealed that this effect may be due largely to up-regulation of CXCR4 expression by SDF-1α on CrFK cells, an effect mimicked by treatment of the cells with phorbol myristate acetate. The data suggest that infection of feline cells with FIV can be mediated by CXCR4 and that, depending on the assay conditions, infection can be either inhibited or enhanced by SDF-1α. Infection with FIV may therefore prove a valuable model in which to study the development of novel therapeutic interventions for the treatment of AIDS.