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1
Edwards, Kimberlee, Kristen M. Braun, Glenn Evans, Amod O. Sureka, and Samuel Fan. "Mainstream and sidestream cigarette smoke condensates suppress macrophage responsiveness to interferony." Human & Experimental Toxicology 18, no. 4 (April 1999): 233–40. http://dx.doi.org/10.1191/096032799678839978.
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Sidestream smoke evolves from the smoldering end of a cigarette while the smoker is not puffing, and contributes substantially to environmental tobacco smoke (ETS). In contrast, main stream smoke emerges from the butt end of the cigarette and is mainly inhaled by the smoker. This study was performed to compare the effects of short-term exposure to cigarette smoke condensates prepared from sidestream (CSCSS) and mainstream cigarette smoke (CSC-MS) on macrophage basal metabolism and responsiveness to two different stimuli, bacterial lipopolysaccharide (LPS) and interferony (IFNy). Despite their generation at different temperatures and their different chemical composition, CSC-SS and CSC-MS had similar effects on macrophages. Both enhanced macrophage basal metabolism and responsiveness to LPS. Macrophage responsiveness to IFNy, assessed by their expression of four functional capacities, was suppressed by both CSC-SS and CSC-MS. The four assessed IFNy-inducible functional capacities were: enhanced phagocytosis of immuoglobulin-opsonized sheep red blood cells, TPAinduced peroxide production, class II major histocompatibility complex expression, and nitric oxide synthesis with LPS co-stimulation. The effects of CSCSS and CSC-MS were similar qualitatively; they differ quantitatively in some cases, with CSC-MS generally effective at lower concentrations (expressed as cigarette-equivalents) than CSCSS. Considering dilution of sidestream smoke in room air and loss during passage through the respiratory system, we expect to deliver the maximal dose to lung macrophages in situ only in rooms dense with smokers. However, only a fraction ofthe maximal dose can partially suppress induction of some fiuctions, such as nitric oxide production and MHC expression. Macrophages play critical roles in tissue modeling during development. Of particular concern are neonates, whose organs are still undergoing growth and development, and are therefore susceptible to impaired development. If involuntary exposure to ETS hinders induction of macrophage functional capacities by cytokines, then development of the lungs and perhaps other organs would be impaired. In general, since macrophages are potent effectors and regulators of immunity, impairment of their responsiveness to cytokine must disrupt the proper functioning of the immune system.
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Coldbeck-Shackley, Rosa C., Ornella Romeo, Sarah Rosli, Linden J. Gearing, Jodee A. Gould, San S. Lim, Kylie H. Van der Hoek, et al. "Constitutive expression and distinct properties of IFN-epsilon protect the female reproductive tract from Zika virus infection." PLOS Pathogens 19, no. 3 (March 10, 2023): e1010843. http://dx.doi.org/10.1371/journal.ppat.1010843.
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The immunological surveillance factors controlling vulnerability of the female reproductive tract (FRT) to sexually transmitted viral infections are not well understood. Interferon-epsilon (IFNɛ) is a distinct, immunoregulatory type-I IFN that is constitutively expressed by FRT epithelium and is not induced by pathogens like other antiviral IFNs α, β and λ. We show the necessity of IFNɛ for Zika Virus (ZIKV) protection by: increased susceptibility of IFNɛ-/- mice; their “rescue” by intravaginal recombinant IFNɛ treatment and blockade of protective endogenous IFNɛ by neutralising antibody. Complementary studies in human FRT cell lines showed IFNɛ had potent anti-ZIKV activity, associated with transcriptome responses similar to IFNλ but lacking the proinflammatory gene signature of IFNα. IFNɛ activated STAT1/2 pathways similar to IFNα and λ that were inhibited by ZIKV-encoded non-structural (NS) proteins, but not if IFNε exposure preceded infection. This scenario is provided by the constitutive expression of endogenous IFNε. However, the IFNɛ expression was not inhibited by ZIKV NS proteins despite their ability to antagonise the expression of IFNβ or λ. Thus, the constitutive expression of IFNɛ provides cellular resistance to viral strategies of antagonism and maximises the antiviral activity of the FRT. These results show that the unique spatiotemporal properties of IFNε provides an innate immune surveillance network in the FRT that is a significant barrier to viral infection with important implications for prevention and therapy.
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Liu, Bi-Sheng, Harry L. A. Janssen, and André Boonstra. "IL-29 and IFNα differ in their ability to modulate IL-12 production by TLR-activated human macrophages and exhibit differential regulation of the IFNγ receptor expression." Blood 117, no. 8 (February 24, 2011): 2385–95. http://dx.doi.org/10.1182/blood-2010-07-298976.
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Abstract The interferon-λ (IFNλ) family of cytokines, consisting of interleukin-28A (IFNλ2), IL-28B (IFNλ3), and IL-29 (IFNλ1), have been extensively studied for their antiviral activities. However, little is known about the effect of IFNλ on antigen-presenting cells. In the present study, we show for the first time that IL-29 can increase Toll-like receptor (TLR)–induced IL-12p40 production by human monocyte-derived macrophages. In contrast, IL-29 did not affect monocytes or monocyte-derived dendritic cells (DCs) because of restricted IL-28 receptor α chain expression by macrophages. Furthermore, IL-29–treated macrophages were more responsive to IFNγ, because IL-29 enhanced IFNγ-induced IL-12p40 and tumor necrosis factor (TNF) production by macrophages on R848 stimulation. However, IFNα suppressed IFNγ-induced IL-12p40 and tumor necrosis factor TNF production by human macrophages. The differential effects of IL-29 and IFNα on the responsiveness of macrophages to IFNγ could not be explained by an effect on TLR7 or TLR8 mRNA expression or by altered IL-10 signaling. However, we demonstrated that IL-29 up-regulated, whereas IFNα down-regulated, the surface expression of the IFNγ receptor 1 chain on macrophages, thereby resulting in differential responsiveness of TLR-challenged macrophages to IFNγ. Our findings on the differences between IFNα and IL-29 in modulating TLR-induced cytokine production by macrophages may contribute to understanding the role of IFNs in regulating immunity to pathogens.
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Lortat-Jacob, H. "Interferon and heparan sulphate." Biochemical Society Transactions 34, no. 3 (May 22, 2006): 461–64. http://dx.doi.org/10.1042/bst0340461.
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In 1954, substances that protected cells from viral infection were discovered and named IFN (interferon). This family of cytokines, which were the first to be used in clinical therapy, is classified into type I and II IFNs. Type I mainly consists of IFNα and IFNβ subtypes, which are structurally related and bind to a common receptor. IFNγ, the sole type II IFN, is structurally unrelated, binds to a different receptor and, as a dimer, strongly interacts with HS (heparan sulphate). In addition to its antiviral activity, it modulates nearly all phases of immune and inflammatory responses. IFNγ binding to HS controls the blood clearance, the subsequent tissue targeting and the local accumulation of the cytokine. It also regulates IFNγ activity by a unique mechanism involving a controlled processing of the C-terminal peptide. The binding site encompasses an N-acetylated glucosamine-rich domain separating two highly sulphated sequences that each binds to one IFNγ monomer. Based on this template, a set of glycoconjugate mimetics that would mimic the IFNγ binding site has been synthesized. One of these molecules displays high affinity for the cytokine and inhibits binding to both HS and IFNγR (IFNγ receptor), the cell-surface receptor. These results validate the HS structural determinants for IFNγ recognition, and provide a new strategy to inhibit IFNγ in a number of diseases in which the cytokine has been identified as a target.
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Hamilton, Jennie A., Qi Wu, PingAr Yang, Bao Luo, Shanrun Liu, Jun Li, Huixian Hong, et al. "Single cell analysis revealed distinct B-cell subpopulations that produce or respond to type I interferon in SLE." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 40.12. http://dx.doi.org/10.4049/jimmunol.200.supp.40.12.
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Abstract We previously showed that B-cell endogenous expression of interferon beta (IFNβ) is associated with the development of autoreactive B cells in BXD2 autoimmune mice. As among all type I IFNs, IFNβ exhibits the highest affinity to IFNAR1 and IFNAR2 and IFNβ also can stimulate IFNαs, there is a pressing need for a better understanding of the source and responses of IFNβ in systemic lupus erythematosus (SLE). Flow cytometry and super-resolution imaging analysis showed increased expression of IFNβ in B cells obtained from PBMCs of SLE patients compared to healthy controls. The importance of SLE B-cell endogenous IFNβ in regulating TLR7-mediated responses was identified when CL264 (a TLR7 ligand) plus anti-Ig-induced CD69 and survival of purified B cells were significantly and equivalently suppressed by an anti-IFNβ or an anti-IFNAR1 blocking antibody. We next carried out single cell qRT-PCR analysis to determine if B-cell endogenous IFNβ acts in an autocrine or paracrine manner to modulate IFN stimulated genes (ISGs). Hierarchical analysis revealed three prominent and consistent clusters, consisting of an IFNB+ cluster, an ISG+ cluster, and an IFNA+ cluster in naïve B cells isolated from 3 SLE patients. Cells within the IFNB+ cluster expressed higher levels of IFNB, IFNA1, IFNA8, and TLR7. Cells within the ISG+ cluster expressed higher levels of IFNAR1, IFNAR2, BAFFR, MX1, RIG1 and TLR9. Cells within the IFNA+ cluster expressed higher levels of IFNA4, IFNA10, IFNA14, IFNA16, IFNA17, and TLR3. Together, the results reveal (1) B cells as an important source of IFNβ in modulating TLR7 responses in SLE; (2) a well-orchestrated program in modulating IFNβ donor versus responder B cells; and (3) some patients may benefit from specific targeting of IFNβ.
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Pizutelli, Vanessa, Carley Tasker, Lishan Sue, Wuyuan Lu, and Theresa Chang. "Human IFNe and IFNa modulate immune and anti-HIV functions through the differential involvement of IFNa receptors." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 66.5. http://dx.doi.org/10.4049/jimmunol.202.supp.66.5.
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Abstract Interferon e (IFNe) is a critical innate immune mediator that protects the host against sexually transmitted infections. Although the current paradigm is that IFNɛ is a type I IFN and signals through IFNa receptors (IFNARs), our and other published results show that IFNɛ has unique gene regulatory and immune functions that are distinct from IFNa. IFNɛ is constitutively expressed in the mucosa, and highly abundant in the female reproductive tract. It exhibits superior mucosal immune activity compared to IFNa/b. We have previously shown that that human IFNe induces an anti-HIV state through a mechanism independent of known type I IFN-induced HIV host restriction factors in primary macrophages. IFNɛ induces phagocytosis and reactive oxygen species that contribute to anti-HIV activity. In this study, we determined the involvement of IFNARs in immune modulation and HIV inhibition by human IFNɛ in comparison to human IFNa. Human IFNɛ elicited a more robust immune response than human IFNa2 in PBMCs and primary macrophages. The immune profiles in response to human IFNɛ were cell-type dependent. Antibodies (Abs) against IFNAR1 or IFNAR2 blocked induction of interferon-stimulated genes (ISGs) by human IFNa2 and murine IFNe. However, anti-IFNAR2 but not anti-IFNAR1 Ab blocked human IFNe-mediated ISG induction. Interestingly, anti-IFNAR1 or anti-IFNAR2 Ab blocked cytokine induction by human IFNa2 but not by human IFNe. Finally, we found that both IFNAR1 and IFNAR2 were involved in anti-HIV activity of human IFNa2 but only IFNAR2 was involved in HIV inhibition by human IFNe. In summary, our results indicate that human IFNe, not a conventional type I IFN, modulates immune and anti-HIV functions through distinct mechanisms from IFNa2.
7
Chang, Theresa Li-Yun, Carley Tasker, Selvakumar Subbian, Pan Gao, Jennifer Couret, Carly Levin, Saleena Ghanny, et al. "Interferon epsilon protects primary macrophages against HIV infection." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 158.15. http://dx.doi.org/10.4049/jimmunol.198.supp.158.15.
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Abstract Interferon epsilon (IFNe) is a unique type I IFN that is not induced by pattern-recognition response elements. IFNɛ is constitutively expressed in mucosal tissues including the female genital mucosa. Although the direct anti-viral activity of IFNe was thought to be weak compared to IFNa, IFNe controls Chlamydia muridarum and herpes simplex virus 2 in mice, possibly through modulation of immune response. We show here that IFNe induces an antiviral state in human macrophages that blocks HIV-1 replication. IFNe had little or no protective effect in activated CD4+ T cells or transformed cell lines unless activated CD4+ T cells were infected with replication competent HIV-1 at a low MOI. The block to HIV infection of macrophages was maximal after 24 h of treatment and was reversible. IFNe acted on early stages of the HIV life cycle including viral entry, reverse transcription and nuclear import. The protection did not appear to operate through known type I IFN-induced HIV host restriction factors such as APOBEC3A and SAMHD1. IFNe-stimulated immune mediators and pathways had the signature of type I IFNs but were distinct from IFNα2. IFNe induced significant phagocytosis and reactive oxygen species, which contributed to the block to HIV replication in macrophages. These findings indicate that IFNe induces an antiviral state in macrophages that is mediated by different factors than those induced by IFNa2. Understanding the mechanism of IFNe-mediated HIV inhibition through immune modulation has implications for prevention.
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Li, Yuanyuan, Yueqi Song, Leqing Zhu, Xiao Wang, Brittany Richers, Donald Y. M. Leung, and Lianghua Bin. "Interferon Kappa Is Important for Keratinocyte Host Defense against Herpes Simplex Virus-1." Journal of Immunology Research 2020 (January 3, 2020): 1–8. http://dx.doi.org/10.1155/2020/5084682.
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Type I interferon kappa (IFNκ) is selectively expressed in human keratinocytes. Herpes simplex virus-1 (HSV-1) is a human pathogen that infects keratinocytes and causes lytic skin lesions. Whether IFNκ plays a role in keratinocyte host defense against HSV-1 has not been investigated. In this study, we found that IFNκ mRNA expression was induced by addition of recombinant IFNκ and poly (I:C); and its expression level was significantly greater than IFNa2, IFNb1, and IFNL1 in both undifferentiated and differentiated normal human epidermal keratinocytes (NHEKs) under resting and stimulation conditions. Although IFNe was expressed at a relatively higher level than other IFNs in resting undifferentiated NHEK, its expression level did not change after stimulation with recombinant IFNκ and poly (I:C). HSV-1 infection inhibited gene expression of IFNκ and IFNe in NHEK. Silencing IFNκ in NHEK led to significantly enhanced HSV-1 replication in both undifferentiated and differentiated NHEK compared to scrambled siRNA-transfected cells, while the addition of recombinant IFNκ significantly reduced HSV-1 replication in NHEK. In addition, we found that IFNκ did not regulate protein expression of NHEK differentiation markers. Our results demonstrate that IFNκ is the dominant type of IFNs in keratinocytes and it has an important function for keratinocytes to combat HSV-1 infection.
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Nguyen, Benjamin H., Elizabeth Troisi, and Diane E. Griffin. "Interferon Regulatory Factor 7-mediated induction of interferon-α is required for survival from alphavirus encephalomyelitis." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 75.35. http://dx.doi.org/10.4049/jimmunol.210.supp.75.35.
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Abstract Alphaviruses are a group of arthropod-borne viruses that have the capacity to cause encephalomyelitis, which is inflammation of the brain and spinal cord due to the immune response to viral infection, and can result in fever, headache, and neurologic disease such as cognitive impairment, seizures, ataxia, and paralysis. Neurons are the primary target cells of Sindbis virus (SINV), the prototypic alphavirus; however, due to the indispensable nature of neurons, mechanisms of viral clearance from the central nervous system (CNS) during recovery cannot depend on immune-mediated killing of infected neurons and is therefore specialized. We have previously shown that interferon (IFN) regulatory factor (IRF) 7, a transcription factor important for amplification of type I IFN (mainly IFNα), is required for survival from infection with SINV. Mice deficient in IRF7 succumb to infection – despite local production of IFNβ – while wild type (WT) mice recover. Treatment of Irf7−/−mice with IFNα rescues the WT phenotype, suggesting that IRF7-mediated induction of IFNα and subsequent downstream signaling is required for survival from SINV infection. Additionally, Ifnb−/−mice do not phenocopy Irf7−/−mice, further suggesting that IFNα is required for survival while IFNβ is dispensable despite usage of the same receptor. Interestingly, Ifnb−/−mice have similar viral titers to Irf7−/−mice, implying that the protective effects of IFNα are independent from restriction of viral replication. These findings show subtype-specific differences in protection by type I IFN and can inform treatment options for alphavirus-induced encephalomyelitis. These works have been funded by the U.S. National Institutes of Health (R01 NS087539 and T32 AI007417).
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Chen, Bohan, Chandan Gurung, Jason Guo, Chulan Kwon, and Yan-Lin Guo. "Pluripotent stem cells are insensitive to the cytotoxicity of TNFα and IFNγ." Reproduction 160, no. 4 (October 2020): 547–60. http://dx.doi.org/10.1530/rep-20-0215.
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Recent studies have demonstrated that embryonic stem cells (ESCs) have an underdeveloped innate immune system, but the biological implications of this finding are poorly understood. In this study, we compared the responses of mouse ESCs (mESCs) and mESC differentiated fibroblasts (mESC-FBs) to tumor necrosis factor α (TNFα) and interferons (IFNs). Our data revealed that TNFα, IFNα, IFNβ, or IFNγ alone do not cause apparent effects on mESCs and mESC-FBs, but the combination of TNFα and IFNγ (TNFα/IFNγ) showed toxicity to mESC-FBs as indicated by cell cycle inhibition and reduced cell viability, correlating with the expression of inducible nitric oxide synthase (iNOS). However, none of these effects were observed in mESCs that were treated with TNFα/IFNγ. Furthermore, mESC-FBs, but not mESCs, are vulnerable to cytotoxicity resulting from lipopolysaccharide (LPS)-activated macrophages. The insensitivity of mESCs to cytotoxicity in all cases is correlated with their lack of responses to TNFα and IFNγ. Similar to mESCs, human ESCs (hESCs) and iPSCs (hiPSCs) do not respond to TNFα and are not susceptible to the cytotoxicity of TNFα, IFNβ, or IFNγ alone or in combination that significantly affects human foreskin fibroblast (hFBs) and Hela cells. However, unlike mESCs, hESCs and hiPSCs can respond to IFNγ, but this does not cause significant cytotoxicity in hESCs and hiPSCs. Our findings in both mouse and human PSCs together support the hypothesis that attenuated innate immune responses could be a protective mechanism that limits immunologic cytotoxicity resulting from inflammatory and immune responses.
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Marín Sánchez, Obert, Dan Vivas-Ruiz, Miguel Neira, Gustavo A. Sandoval, Olegario Marín- Machuca, Ana Juliet Rodriguez-Landauro, and Ruy D. Chacón. "Rol de los interferones tipo I y tipo III: Una revisión de conceptos." Revista Científica Ágora 6, no. 2 (December 27, 2019): e6. http://dx.doi.org/10.21679/arc.v6i2.133.
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Los interferones (IFN), inicialmente denominados como “mediadores solubles que interfieren con la infección celular por el virus de la gripe A”, son familias de proteínas secretadas que regulan la inmunidad innata y adquirida tras la activación de receptores de reconocimiento de patrones (PRR). Los IFN tienen un impacto en los procesos de proliferación, diferenciación y muerte celular. Los IFN, dependiendo de las características moleculares del gen que lo codifica y los receptores diana, se dividen en tres familias: IFN tipo I (IFNα, IFNβ, IFNω, IFNτ, IFNε), tipo II (IFNγ) y tipo III (IFNλ1, IFNλ2/3, IFN λ4). En este contexto, la presente revisión brinda los principales conceptos sobre los interferones tipo I y tipo III dado que ambos comparten la misma cascada de señalización; aunque, el mecanismo de acción de IFN tipo III, sea aún poco conocido, estos pueden ser empleados como agentes biológicos en comparación los IFN tipo I.
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Francois-Newton, Véronique, Mark Livingstone, Béatrice Payelle-Brogard, Gilles Uzé, and Sandra Pellegrini. "USP18 establishes the transcriptional and anti-proliferative interferon α/β differential." Biochemical Journal 446, no. 3 (August 28, 2012): 509–16. http://dx.doi.org/10.1042/bj20120541.
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Type I IFNs (interferons) are pathogen-induced immunoregulatory cytokines that exert anti-viral and anti-proliferative activities through binding to a common cell-surface receptor. Among the 17 human IFN subtypes, IFNβ binds the IFNAR (IFNα receptor) 1/IFNAR2 receptor chains with particularly high affinity and is especially potent in select bioactivities (e.g. anti-proliferative and pro-apoptotic) when compared with IFNα2. However, no molecular basis has been ascribed to this differential action, since the two ligands are equipotent in immediate early signalling events. In the present study we report that IFNβ induces Stat (signal transducer and activator of transcription) phosphorylation and transcriptional activation of ISGs (interferon-stimulated genes), including two genes with pro-apoptotic functions, for a considerably longer time frame than does IFNα2. We show that the diversification of α2/β responses progressively builds up at the receptor level as a result of accumulating USP18 (ubiquitin specific protease 18), itself an ISG, which exerts its negative feedback action by taking advantage of the weakness of IFNα2 binding to the receptor. This represents a novel type of signalling regulation that diversifies the biological potential of IFNs α and β.
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Khan, O. A., H. Jiang, P. S. Subramaniam, H. M. Johnson, and S. S. Dhib-Jalbut. "Immunomodulating functions of recombinant ovine interferon tau: potential for therapy in mulitple sclerosis and autoimmune disorders." Multiple Sclerosis Journal 4, no. 2 (April 1998): 63–69. http://dx.doi.org/10.1177/135245859800400204.
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The interferons (IFN) are a family of complex proteins possessing antiviral, antiproliferative, and immunomodulatory activities. Two type 1 recombinant human IFN have been recently approved for the treatment of multiple sclerosis (MS). However, use of high dose type 1 IFN treatment in MS patients has been limited by dose-related toxicity. Ovine IFNt is a unique type 1 interferon discovered for its role in the animal reproductive cycle. It differs from other type 1 IFNs in that it is remarkably less toxic even at high concentrations, is able to cross species barriers, and is not inducible by viral infection. Ovine IFNt has been shown to be very effective in the treatment of animal models of MS. In this study, we examined the toxicity of OvIFNt on human T-cells at high doses and its immunregulatory properties at equivalent doses. Our experiments confirmed the remarkably non-toxic nature of OvIFNt on human cells at high concentrations as well as immunomodulating properties consistent with other type 1 IFNs including an antilymphoproliferative effect and inhibition of IFNg-induced HLA class II expression. These results suggest that OvIFNt could be developed into a potentially less toxic therapeutic option for immune-mediated disorders including MS.
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Winterberg, Pamela D., Yanxia Wang, Keng-Mean Lin, John R. Hartono, Glenn T. Nagami, Xin J. Zhou, John M. Shelton, James A. Richardson, and Christopher Y. Lu. "Reactive oxygen species and IRF1 stimulate IFNα production by proximal tubules during ischemic AKI." American Journal of Physiology-Renal Physiology 305, no. 2 (July 15, 2013): F164—F172. http://dx.doi.org/10.1152/ajprenal.00487.2012.
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We previously reported that expression of the transcription factor interferon regulatory factor 1 (IRF1) is an early, critical maladaptive signal expressed by renal tubules during murine ischemic acute kidney injury (AKI). We now show that IRF1 mediates signals from reactive oxygen species (ROS) generated during ischemic AKI and that these signals ultimately result in production of α-subtypes of type I interferons (IFNαs). We found that genetic knockout of the common type I IFN receptor (IFNARI−/−) improved kidney function and histology during AKI. There are major differences in the spatial-temporal production of the two major IFN subtypes, IFNβ and IFNαs: IFNβ expression peaks at 4 h, earlier than IFNαs, and continues at the same level at 24 h; expression of IFNαs also increases at 4 h but continues to increase through 24 h. The magnitude of the increase in IFNαs relative to baseline is much greater than that of IFNβ. We show by immunohistology and study of isolated cells that IFNβ is produced by renal leukocytes and IFNαs are produced by renal tubules. IRF1, IFNαs, and IFNARI were found on the same renal tubules during ischemic AKI. Furthermore, we found that ROS induced IFNα expression by renal tubules in vitro. This expression was inhibited by small interfering RNA knockdown of IRF1. Overexpression of IRF1 resulted in the production of IFNαs. Furthermore, we found that IFNα stimulated production of maladaptive proinflammatory CXCL2 by renal tubular cells. Altogether our data support the following autocrine pathway in renal tubular cells: ROS > IRF1 > IFNα > IFNARI > CXCL2.
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Pinacchio, Claudia, Giuseppe Corano Scheri, Maura Statzu, Letizia Santinelli, Giancarlo Ceccarelli, Giuseppe Pietro Innocenti, Vincenzo Vullo, et al. "Type I/II Interferon in HIV-1-Infected Patients: Expression in Gut Mucosa and in Peripheral Blood Mononuclear Cells and Its Modification upon Probiotic Supplementation." Journal of Immunology Research 2018 (August 12, 2018): 1–7. http://dx.doi.org/10.1155/2018/1738676.
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Expression of type I and II interferon (IFN) was evaluated in gut-associated lymphoid tissue (GALT) and peripheral blood mononuclear cells (PBMCs) of HIV-1-positive patients on long-term, suppressive, antiretroviral therapy before and after probiotic supplementation. IFNα subtypes and IFNβ were expressed at higher levels in GALT compared to PBMC, whereas an opposite trend of expression was recorded for IFNγ. An increase of IFNα6, IFNα10, IFNα14, IFNα17, and IFNα21 and a decrease of IFNγ were observed in both anatomical sites after probiotic supplementation.
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Antipova, A. Yu, V. G. Drobyshevskaia, and I. V. Khamitova. "Case of parvovirus B19 infection and immunodeficiency in the patient with Gilbert syndrome." Medical Immunology (Russia) 23, no. 5 (November 17, 2021): 1177–82. http://dx.doi.org/10.15789/1563-0625-cop-2325.
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A case of long-term persistence of parvovirus B19 is described for the first time in a patient with Gilbert's syndrome against the background of immunodeficiency with predominance of infectious symptoms (chronic herpesvirus infection). Previously, the patient (male, 48 years old) was diagnosed with Gilbert's syndrome, chronic rhinosinusopharyngitis, and chronic herpesvirus infection. In July 2017, parvovirus B19 DNA was detected in blood. No clinical manifestations of infectious erythema were noted. The patient was admitted to the medical center of St. Petersburg Pasteur Institute. His blood samples obtained under informed consent were examined at the medical center in Central Clinical and Diagnostic Laboratory of St. Petersburg Pasteur Institute in January and June 2018 and in November 2019. ELISA test systems “Anti-Parvovirus B19 ELISA (IgM)” and “Anti-Parvovirus B19 ELISA (IgG)” (Euroimmune, Germany), as well PCR reagent kit “AmpliSens Parvovirus B19-FL” (FSB Central Research Institute of Epidemiology of Rospotrebnadzor, Russia) were used for specific diagnostics. Interferon status was determined by the induced production of IFN types I, II and circulating (serum) interferons. Moreover, we considered the laboratory data obtained earlier at different medical facilities of St. Petersburg. IgM class antibodies to the parvovirus B19 were not detected in the blood samples obtained in 2018. IgG antibody titer was 96 IU/ml and 264 IU /ml, respectively. Parvovirus B19 DNA was isolated from blood plasma, but the viral load was less than 720 IU of PVB19 DNA/ml (1.5 x 102 and 1.9 x 102 copies of DNA/ml, respectively). Clinical blood analysis, showed only minor (no more than 7%) deviations from the reference values, increased hemoglobin saturation of red blood cells (RBC), a decreased width of RBC distribution curve, and relative lymphocytosis. A deficiency of various interferon types was revealed: IFNγ level was 80 IU/ml in both samples, IFNα, IFNβ amounts varied from 80 to 160 IU/ml, respectively. The period of parvovirus B19 DNA persistence in blood was 11 months in presence of immunodeficiency. The patient was administered drugs of the interferon group. Parvovirus B19 DNA was not detected in clinical samples of November 2019; IFNα, IFNβ and IFNγ values were 160 IU/ml. We have detected recovery of lymphoid cell ratio, increase in their number, and improved indexes of interferon status.
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Harris, Bethany D., Jessica Schreiter, Marc Chevrier, Jarrat L. Jordan, and Mark R. Walter. "Human interferon-ϵ and interferon-κ exhibit low potency and low affinity for cell-surface IFNAR and the poxvirus antagonist B18R." Journal of Biological Chemistry 293, no. 41 (August 31, 2018): 16057–68. http://dx.doi.org/10.1074/jbc.ra118.003617.
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IFNϵ and IFNκ are interferons that induce microbial immunity at mucosal surfaces and in the skin. They are members of the type-I interferon (IFN) family, which consists of 16 different IFNs, that all signal through the common IFNAR1/IFNAR2 receptor complex. Although IFNϵ and IFNκ have unique expression and functional properties, their biophysical properties have not been extensively studied. In this report, we describe the expression, purification, and characterization of recombinant human IFNϵ and IFNκ. In cellular assays, IFNϵ and IFNκ exhibit ∼1000-fold lower potency than IFNα2 and IFNω. The reduced potency of IFNϵ and IFNκ are consistent with their weak affinity for the IFNAR2 receptor chain. Despite reduced IFNAR2-binding affinities, IFNϵ and IFNκ exhibit affinities for the IFNAR1 chain that are similar to other IFN subtypes. As observed for cellular IFNAR2 receptor, the poxvirus antagonist, B18R, also exhibits reduced affinity for IFNϵ and IFNκ, relative to the other IFNs. Taken together, our data suggest IFNϵ and IFNκ are specialized IFNs that have evolved to weakly bind to the IFNAR2 chain, which allows innate protection of the mucosa and skin and limits neutralization of IFNϵ and IFNκ biological activities by viral IFN antagonists.
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Lim, Joanne, Scott Gerber, and Edith Lord. "The importance of type I interferons in radiation-mediated antitumor responses (162.33)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 162.33. http://dx.doi.org/10.4049/jimmunol.188.supp.162.33.
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Abstract Interferon alpha (IFNα) has been FDA-approved for treatment of high-risk melanoma since 1995. Besides having direct antitumor effects, IFNα and IFNβ, the other major type I IFN (IFN-I), have been found to act through enhancing multiple pathways within the host immune system. However, the mechanisms by which IFN-Is mediate these responses remain unclear. Our previous data demonstrated that treatment of in vivo B16 melanoma with a single high dose local radiation induced an increase in IFNγ levels within the tumor microenvironment. Interestingly, this increase is abolished in the absence of IFNα/β signaling within host cells, as observed using IFNα/β receptor knockout mice (KO). Importantly, the induction of downstream IFNγ-dependent genes such as the CXCR3 family of chemokines is also affected. Since CXCR3 chemokines have been shown to be crucial chemoattractants for T cells in tumors, it is not surprising that the lack of IFNα/β receptor also resulted in decreased recruitment of CD8 T cells to tumors in response to radiation treatment. Corresponding to these effects, radiation-treated KO mice exhibit poor tumor growth control compared to wild type mice. Taken together, our data suggest that IFN-Is play a critical role in radiation-mediated antitumor responses. An important mechanism through which this occurs depends on the ability of IFN-Is to enhance IFNγ responses, which in turn upregulates CXCR3 chemokines in the tumor, resulting in enhanced recruitment of CD8 T cells.
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Nunes, Ana Tablante, Daniel Green, Irene Ekwede, Kathryn Zoon, and Christina M. Annunziata. "Phase 1 study of intraperitoneal infusion of autologous monocytes with peginterferon alfa-2b and interferon gamma-1b in women with recurrent or refractory ovarian cancer, fallopian tube cancer, or primary peritoneal cancer." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): TPS3092. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps3092.
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TPS3092 Background: Monocytes can differentiate into classic M1 macrophages inhibiting tumor proliferation and promoting natural killer (NK) cell differentiation. We previously demonstrated that the combination of human monocytes, human interferon alfa-2b (IFNα-2b), and interferon gamma-1b (IFNγ 1b) act synergistically against tumor cells in vitro and in mouse models, providing a long and durable response. Additionally, monocytes, IFNα and IFNγ have been individually shown in early phase clinical trials to be safely administered intraperitoneally. As ovarian cancer is largely confined to the peritoneal cavity, it is likely that the administration of IFNs and monocytes intraperitoneally will create a strong anti-tumor environment and can overcome the immunosuppressive environment of epithelial ovarian cancer. We hypothesize that the monocyte and interferon administration will be tolerable to women with relapsed ovarian cancer. Methods: A Phase 1 single arm study to determine the maximum tolerated dose of intraperitoneal monocytes and pegylated IFNα-2b and IFNγ-1b is currently enrolling patients with recurrent or refractory ovarian cancer, fallopian tube cancer or primary peritoneal cancer without standard therapy options. Autologous monocytes obtained through apheresis 24 hours prior will be mixed with pegylated IFNα-2b and IFNγ-1b in a 3 + 3 dose escalation and administered intraperitoneally once every 28 days. Results: As of February 2017 we are enrolling our first cohort of patients and are evaluating for dose limiting toxicities. Conclusions: This is a novel therapy that if successful, may be efficacious alone or used to create a backbone on which to add novel agents such as SMAC mimetics or PD-L1 blockade, in order to increase immune-mediated killing of ovarian cancer. Clinical trial information: NCT 02948426.
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Ealy, Alan D., and Lydia K. Wooldridge. "The evolution of interferon-tau." Reproduction 154, no. 5 (November 2017): F1—F10. http://dx.doi.org/10.1530/rep-17-0292.
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Thirty years ago, a novel type I interferon (IFN) was identified by molecular cloning of cDNA libraries constructed from RNA extracted from ovine and bovine pre-implantation embryos. This protein was eventually designated as IFN-tau (IFNT) to highlight its trophoblast-dependent expression. IFNT function is not immune related. Instead, it interacts with the maternal system to initiate the establishment and maintenance of pregnancy. This activity is indispensable for the continuation of pregnancy. Our review will describe how IFNT evolved from other type I IFNs to function in this new capacity. IFNT genes have only been identified in pecoran ruminants within the Artiodactyla order (e.g. cattle, sheep, goats, deer, antelope, giraffe). The ancestral IFNT gene emerged approximately 36 million years ago most likely from rearrangement and/or insertion events that combined an ancestral IFN-omega (IFNW) gene with a trophoblast-specifying promoter/enhancer. Since then, IFNT genes have duplicated, likely through conversion events, and mutations have allowed them to adapt to their new function in concert with the emergence of different species. Multiple IFNT polymorphisms have been identified in cattle, sheep and goats. These genes and gene alleles encode proteins that do not display identical antiviral, antiproliferative and antiluteolytic activities. The need for multiple IFNT genes, numerous alleles and distinct activities remains debatable, but the consensus is that this complexity in IFNT expression and biological activity must be needed to provide the best opportunity for pregnancy to be recognized by the maternal system so that gestation may continue.
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Crisler, William J., Emily M. Eshleman, and Laurel L. Lenz. "Type I and II IFNs differentially regulate IFNGR1 to tune IFNγ responsiveness in myeloid cells." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 169.7. http://dx.doi.org/10.4049/jimmunol.200.supp.169.7.
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Abstract Interferons (IFNs) act on macrophages to shape immune responses against microbial infections and tumors. Type I and II IFNs signal to induce transcription of IFN-stimulated genes (ISGs). Binding of the type II IFN (IFNγ) to its receptor, IFNGR, induces ISGs that enhance macrophage inflammatory and anti-microbial activity critical for bacterial infection. Conversely, when type I IFNs bind their receptor (IFNAR), they reduce expression of myeloid cell surface IFNGR and dampen macrophage responsiveness to IFNγ. Macrophages stimulated with IFNγ also reduce cell surface IFNGR, but this was previously attributed to ligand-induced receptor internalization. Here, we confirm the ability of IFNγ stimulation to rapidly reduce cell surface IFNGR in cultured mouse and human macrophages. However, we find this ligand-induced reduction in IFNGR is associated with reduced ifngr1 transcript abundance. Unlike IFNβ, IFNγ did not impede de novo transcription from an ifngr1 promoter-driven reporter construct, suggesting IFNγ reduces ifngr1 transcript abundance via a distinct mechanism. BMDMs pulsed with IFNγ transiently became refractory to a secondary IFNγ treatment as measured by impaired STAT1 phosphorylation. As shown previously, type I IFNs cause a reduction in myeloid cell surface IFNGR1 seen 72 hpi with systemic L. monocytogenes (Lm), and this reduction was abrogated by myeloid cell expression of a transgenic IFNGR1 in fGR1 mice. In contrast, IFNγ was responsible for a reduction in IFNGR on myeloid cells early after systemic Lm infection (24 hip), and this was not abrogated in fGR1 mice. Together, our results demonstrate that type I and II IFNs act via distinct mechanisms to prevent hyper-activation of myeloid cells following exposure to IFNγ.
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Bertzbach, Luca D., Olof Harlin, Sonja Härtle, Frank Fehler, Tereza Vychodil, Benedikt B. Kaufer, and Bernd Kaspers. "IFNα and IFNγ Impede Marek’s Disease Progression." Viruses 11, no. 12 (November 28, 2019): 1103. http://dx.doi.org/10.3390/v11121103.
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Marek’s disease virus (MDV) is an alphaherpesvirus that causes Marek’s disease, a malignant lymphoproliferative disease of domestic chickens. While MDV vaccines protect animals from clinical disease, they do not provide sterilizing immunity and allow field strains to circulate and evolve in vaccinated flocks. Therefore, there is a need for improved vaccines and for a better understanding of innate and adaptive immune responses against MDV infections. Interferons (IFNs) play important roles in the innate immune defenses against viruses and induce upregulation of a cellular antiviral state. In this report, we quantified the potent antiviral effect of IFNα and IFNγ against MDV infections in vitro. Moreover, we demonstrate that both cytokines can delay Marek’s disease onset and progression in vivo. Additionally, blocking of endogenous IFNα using a specific monoclonal antibody, in turn, accelerated disease. In summary, our data reveal the effects of IFNα and IFNγ on MDV infection and improve our understanding of innate immune responses against this oncogenic virus.
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Muttar, A. A. "Cloning and gene expression equine leukocyte α-interferon in cells of Escherichia Coli." Al-Qadisiyah Journal of Veterinary Medicine Sciences 12, no. 1 (June 30, 2013): 82. http://dx.doi.org/10.29079/vol12iss1art234.
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Interferon plays role in innate immune responses through upregulation of costimulatory molecules and induction of proinflammatory cytokines. interferons including interferon alpha (IFNA). The present study characterized IFNA cDNA and predicted protein. The interferon’s play a great role in protection from infections, which have been called by microorganisms, and also have powerful antiproliferation and immunomodulation activity. The purposes of study: cloning and expression of horse leukocyte interferon and purification the product protein. The results and discussion : In the result we isolated (DNA) from equine leukocyte in blood, which was used in the quality of the matrix for amplification of α-interferon gene with PCR HELP, and isolation gene α-interferon and transformation in vector puc18 and expression vector PET24b (+) and recombinant plasmid was transformed into E. coli strain BL21( codon plus 440) induction with IPTG. The results showed the protein having the same molecular weight as horse interferon alpha about 5.81 kDa
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Filipi, Mary, and Samantha Jack. "Interferons in the Treatment of Multiple Sclerosis." International Journal of MS Care 22, no. 4 (October 30, 2019): 165–72. http://dx.doi.org/10.7224/1537-2073.2018-063.
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Abstract Interferon beta (IFNβ) was the first disease-modifying therapy available to treat multiple sclerosis (MS), providing patients with a treatment that resulted in reduced relapse rates and delays in the onset of disability. Four IFNβ drugs are currently approved to treat relapsing forms of MS: subcutaneous (SC) IFNβ-1b, SC IFNβ-1a, intramuscular IFNβ-1a, and, most recently, SC peginterferon beta-1a. Peginterferon beta-1a has an extended half-life and requires less frequent administration than other available treatments (once every 2 weeks vs every other day, 3 times per week, or weekly). Large randomized controlled clinical trials have confirmed the efficacy of interferons for the treatment of relapsing MS. The most frequent adverse events in patients receiving IFNs include injection site reactions and flu-like symptoms. Patient education and mitigation strategies are key to managing these adverse events and supporting therapy adherence. With fewer injections needed, peginterferon beta-1a is associated with less frequent discomfort, which may translate to improved adherence, a major factor in treatment efficacy. Because the available interferon therapies differ in administration route and frequency of injection, switching among these therapies may be a viable option for patients who experience issues with tolerability. Although a variety of disease-modifying therapies are now available to treat relapsing MS, the efficacy and long-term safety profile of interferons make them an important first-line option for treatment.
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Li, Aidan, Xuetao Bai, Na Li, Shurui Cai, Ananya Banerjee, Kousalya Lavudi, Linzhou Wang, Qianyun Ge, Yajing Yang, and Qi-En Wang. "Abstract 2428: Cancer stem cells maintain stemness via autocrine activation of the IFN/JAK/STAT signaling pathway." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2428. http://dx.doi.org/10.1158/1538-7445.am2023-2428.
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Abstract Interferons (IFNs) and Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling are best known for their roles in immunity. However, recent work has suggested that both IFNs and the JAK/STAT pathways are associated with tumor growth and progression, as well as the maintenance of cancer stem cell (CSC) populations. To better understand the regulation of the CSC population maintenance by the IFN/JAK/STAT signaling pathway, we enriched CSCs from a panel of non-small cell lung cancer (NSCLC) cell lines by using spheroid culture and determined the phosphorylation of STAT1. We found that sphere cells exhibit increased level of pSTAT1-Y701 compared to their corresponding bulk cells. We further determined the expression level of a few interferon-stimulated genes (ISGs) and found that sphere cells possess enhanced expression of ISG54 and ISG56 genes, which are normally induced by type I IFN (IFN-I), as well as IFNA and IFNB. These results indicate that the IFN-I/STAT1 signaling is highly activated in CSCs, which produce and secrete increased amount of IFN-I. To directly show the effect of IFN-I on the stemness of NSCLC cells, we treated NSCLC cells with IFNβ, and found that IFNβ can significantly enhance the expression of SOX2, a stem cell-specific transcription factor; Inhibition of the JAK signaling blocked both basal and IFNβ-induced SOX2 expression. In addition, knockdown of STAT1 also reduced SOX2 expression, indicating that STAT1 activation plays an important role in mediating IFN-induced enhancement of stemness. Finally, the ChIP assay demonstrated that STAT1 protein can bind to the promoter region of the SOX2 gene to serve as a transcription factor. In summary, our results indicate that CSCs produce and secrete IFN-I via their enhanced JAK/STAT1 signaling. The secreted IFN-I can bind to the receptor on the CSCs, further activate their JAK/STAT1 signaling, promoting the expression of SOX2 and maintenance of stemness of CSCs via an autocrine manner. Citation Format: Aidan Li, Xuetao Bai, Na Li, Shurui Cai, Ananya Banerjee, Kousalya Lavudi, Linzhou Wang, Qianyun Ge, Yajing Yang, Qi-En Wang. Cancer stem cells maintain stemness via autocrine activation of the IFN/JAK/STAT signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2428.
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Bauersachs, S., S. E. Ulbrich, H. D. Reichenbach, M. Reichenbach, M. Büttner, H. H. D. Meyer, T. E. Spencer, et al. "83 EFFECTS OF HUMAN INTERFERON-α ON GENE EXPRESSION IN THE BOVINE ENDOMETRIUM IN COMPARISON TO DAYS 15 AND 18 OF PREGNANCY." Reproduction, Fertility and Development 24, no. 1 (2012): 154. http://dx.doi.org/10.1071/rdv24n1ab83.
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Interferon-τ (IFNT), a Type-I interferon (IFN), is the pregnancy recognition signal produced by the ruminant conceptus (Godkin et al. 1984; Hansen et al. 1985; Helmer et al. 1987; Spencer et al. 2007). In addition to these specific functions of IFNT in ruminants, many studies suggest that IFNs play a general role in establishment of pregnancy and conceptus attachment/implantation in most mammalian species (Bazer et al. 2009; Bazer et al. 2010; Johnson et al. 2009; Roberts et al. 2008). To characterise the effects of prototype Type-I IFNs on bovine endometrium, in experiment one, Simmental heifers were treated from Day 14 to Day 16 of the oestrous cycle with a rod-shaped intrauterine device releasing human interferon-α (IFNA) or placebo lipid extrudates or PBS only as controls (n = 4 each). Lipid formulation and concentration of human IFNA were adjusted to release 8–9 × 107 IU of IFNA over a period of 2 days in in vitro release experiments. On Day 16, endometrial biopsy samples were collected after flushing the uterus. In experiment 2, endometrial tissue samples were obtained on Day 12, 15 and 18 post-mating from nonpregnant or pregnant heifers. All samples from both experiments were analysed with an Affymetrix Bovine Genome Array (Santa Clara, CA). In experiment one, IFNA treatment resulted in differential gene expression in the bovine endometrium. Significant differences were found between the IFNA group and both control groups, whereas no differences were observed between the placebo and the PBS control group. In experiment 2, differentially expressed genes were found between pregnant and nonpregnant endometria on Day 15 and 18, but not on Day 12, with many of them known IFN-stimulated genes. The comparison of the data sets from both experiments showed very similar gene expression changes for most of the typical IFN-stimulated genes. In addition, several genes were identified which were differentially expressed after IFNA treatment but not different at Day 15 or 18 of pregnancy compared with nonpregnant animals. Conversely, some genes were found as differentially expressed during pregnancy but not after IFNA treatment. Differential expression of selected genes was verified by quantitative real-time PCR and 4 genes, namely jumonji C domain containing histone demethylase 1 homologue D (JHDM1D), indoleamine 2,3-dioxygenase 1 (IDO1), fatty acid binding protein 3, muscle and heart (mammary-derived growth inhibitor) (FABP3) and dickkopf homologue 1 (DKK1), were selected for localization of mRNA expression in endometrial tissue sections. The findings of this study suggest that there may be differential effects of bovine IFNT compared with human IFNA and that some pregnancy-specific changes in the endometrium are elicited by conceptus-derived factors other than IFNT. This study was supported by the German Ministry for Education and Research (BMBF, FUGATO-plus, COMPENDIUM) and the German Research Foundation (DFG FOR478). The authors are part of the European Union COST action GEMINI.
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Maślińska, M., A. Paradowska-Gorycka, A. Wajda, K. Kostyra-Grabczak, and B. Kwiatkowska. "THU0277 THE EXPRESSION OF IFNΑ, INFΒ AND INFΓ AND SERUM LEVELS OF THOSE CYTOKINES IN SJÖGREN’S SYNDROME PATIENTS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 365.1–365. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1194.
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Background:In the pathogensis of autoimmune mediated diseases, such as Sjögren’s syndrome (SS), interferons (IFN) and IFN pathway activation play a vital role.Objectives:We planned to assess IFNα, INFβ and INFγ expression and IFNs serum levels in SS patients and correlation of these parameters with: autoantibodies specific for SS, serum concentration of C3, C4 component of complement (C3, C4), rheumatoid factor (RF), gammaglobulins, focus score (FS) and eye dryness symptoms.Methods:Whole blood RNA was isolated from 77 SS patients [F91%vsM9%]; mean age 49,69±15.36; SS diagnosis according to EULAR/ACR 2016 criteria. The analysis of INFα, - β and - γ expression levels was based on validated TaqMan probes by ΔCT methods. Serum concentrations of rheumatoid factor (RF), C3- and C4 complement components (mg/dL) and gammaglobulins (g/dL), were assessed. Anti-Ro/SSA and/or anti-La/SSB autoantibodies were assessed by semiquantitative immunoblotting evaluation. The eye dryness and keratoconjunctivitis sicca were confirmed with Schirmer’s test (score of less than 5 mm/5’) and the ocular staining score (OSS) using lissamine green and fluorescein staining. The biopsy of minor salivary gland was performed with the histopathological evaluation of FS. The study was approved by the Bioethics Committee. Differences between groups of patients were determined using non-parametric Mann-Whitney U test or Kruskall-Wallis test with Dunn’s post hoc. Correlations were determined using non-parametric Spearman test. The level of statistical significance was set at p < 0.05.Results:IFNβ had the highest expression levels among IFNs and IFNβ serum concentrations were higher than those of IFNα and -γ. In cases with high IFNβ serum concentration lower IFNβ expression was observed. There was a highly significant correlation between IFNα and IFNβ expression (r =0.6;p=0.001). IFNβ expression (p=0.059) was higher in the group of younger (<45 y.o.) patients (n= 23; 29.9%) as compared to the group of older individuals (at least 45 y.o.). In patients with SS-A / Ro antibodies with strong antigen binding affinity (3) IFN β expression and IFNβ serum levels were highest of all IFNs. The presence of anti La/SS-B antibodies was associated with the increased IFNβ expression while not with the increased IFNβ serum concentration. In terms of IFNα expression and protein level, RF(+)patients had average higher values compared to RF(-) patients. The average mRNA level of IFNα was about 3 times lower in patients with low C3 serum concentration compared to patients with normal C3 serum concentration values. IFNβ mRNA level was 2.5 times lower in patients with low Schirmer’s test (<5mm/5’) in comparison to patients with Schirmer’s test>5mm/5’; Schirmer’s test <5mm/5’ was associated with higher IFNβ serum concentration.Conclusion:Type I IFN signature predominates in the peripheral blood of studied patients. Presented results confirmed the pivotal role of type I IFN in the disease process. The serum concentration of IFNβ and the expression of IFNβ were the highest values of those parameters for cytokines assessed in this study. A positive correlation between IFNα and IFNβ mRNA levels has been observed.Disclosure of Interests:None declared
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McClary, Heike, Rick Koch, Francis V. Chisari, and Luca G. Guidotti. "Relative Sensitivity of Hepatitis B Virus and Other Hepatotropic Viruses to the Antiviral Effects of Cytokines." Journal of Virology 74, no. 5 (March 1, 2000): 2255–64. http://dx.doi.org/10.1128/jvi.74.5.2255-2264.2000.
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ABSTRACT We have previously shown that hepatitis B virus (HBV) replication is inhibited noncytopathically in the livers of transgenic mice following injection of HBV-specific cytotoxic T lymphocytes (CTLs) or infection with unrelated hepatotropic viruses, including lymphocytic choriomeningitis virus (LCMV) and adenovirus. These effects are mediated by gamma interferon (IFNγ), tumor necrosis factor alpha (TNFα), and IFNα/β. In the present study, we crossed HBV transgenic mice with mice genetically deficient for IFNγ (IFNγKO), the TNFα receptor (TNFαRKO), or the IFNα/β receptor (IFNα/βRKO) in order to determine the relative contribution of each cytokine to the antiviral effects observed in each of these systems. Interestingly, we showed that HBV replicates in unmanipulated IFNγKO and IFNα/βRKO mice at levels higher than those observed in control mice, implying that baseline levels of these cytokines control HBV replication in the absence of inflammation. We also showed that IFNγ mediates most of the antiviral effect of the CTLs while IFNα/β is primarily responsible for the early inhibitory effect of LCMV and adenovirus on HBV replication. In addition, we showed that the hepatic induction of IFNα/β observed after injection of poly(I · C) is sufficient to inhibit HBV replication and that a similar antiviral effect is achieved by systemic administration of very high doses of IFNα. We also compared the relative sensitivity of LCMV and adenovirus to control by IFNγ, TNFα, or IFNα/β in these animals. Importantly, IFNα/βRKO mice, and to a lesser extent IFNγKO mice, showed higher hepatic levels of LCMV RNA and adenovirus DNA and RNA than control mice, underscoring the importance of both interferons in controlling these other viral infections as well.
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May, Dana, Anna Bellizzi, Workineh Kassa, John M. Cipriaso, Maurizio Caocci, and Hassen S. Wollebo. "IFNα and β Mediated JCPyV Suppression through C/EBPβ-LIP Isoform." Viruses 13, no. 10 (September 26, 2021): 1937. http://dx.doi.org/10.3390/v13101937.
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Polyomavirus JC (JCPyV) causes the demyelinating disease progressive multifocal leukoencephalopathy (PML). JCPyV infection is very common in childhood and, under conditions of severe immunosuppression, JCPyV may reactivate to cause PML. JC viral proteins expression is regulated by the JCPyV non-coding control region (NCCR), which contains binding sites for cellular transcriptional factors which regulate JCPyV transcription. Our earlier studies suggest that JCPyV reactivation occurs within glial cells due to cytokines such as TNF-α which stimulate viral gene expression. In this study, we examined interferon-α (IFNα) or β (IFNβ) which have a negative effect on JCPyV transcriptional regulation. We also showed that these interferons induce the endogenous liver inhibitory protein (LIP), an isoform of CAAT/enhancer binding protein beta (C/EBPβ). Treatment of glial cell line with interferons increases the endogenous level of C/EBPβ-LIP. Furthermore, we showed that the negative regulatory role of the interferons in JCPyV early and late transcription and viral replication is more pronounced in the presence of C/EBPβ-LIP. Knockdown of C/EBPβ-LIP by shRNA reverse the inhibitory effect on JCPyV viral replication. Therefore, IFNα and IFNβ negatively regulate JCPyV through induction of C/EBPβ-LIP, which together with other cellular transcriptional factors may control the balance between JCPyV latency and activation.
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Ospelnikova, T. P., O. V. Morozova, S. A. Andreeva, E. I. Isaeva, L. V. Kolodyazhnaya, L. V. Kolobukhina, L. N. Merkulova, E. I. Burtseva, E. A. Mukasheva, and F. I. Ershov. "INFLUENZA INFLAMMATION BIOMARKERS FEATURES." Journal of microbiology epidemiology immunobiology 1, no. 3 (August 25, 2019): 67–73. http://dx.doi.org/10.36233/0372-9311-2018-3-67-73.
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Aim. Analysis of inflammation biomarkers using reverse transcription with real time PCR (RT-PCR-RT) and multiplex immunofluorescent analysis xMAP with magnetic beads for the influenza infection. Materials and methods. Analysis of nasopharyngeal swabs, lymphocytes and blood sera of 10 patients with influenza and 10 donors was performed during the first 2 days of the disease by means of RT-PCR-RT and xMAP using the kit «37-plex» (BioRad). Results.The influenza virus A was revealed in 4 samples, the influenza virus B — in 6 swabs without mixed infections with other respiratory viruses. Analysis of the interferons (IFN) showed IFNα gene expression activation in patients’ lymphocytes but both the detection rate and the concentrations of IFNβ, IFNγ and IFNλ RNA were similar for patients and healthy donors. Among 37 inflammation biomarkers the concentrations of 7 proteins were enhanced including IFNα2, cytokines of TNF family (APRIL and BAFF), their soluble receptors sTNF-R1 and sTNF-R2, protein osteopontin and IL10. The concentrations of the complex of glycoprotein gp130 with the soluble receptor IL6 gp130/sIL-6Rβ and the matrix metalloprotease ММР-1 were reduced in patients’ sera. The polarization coefficient PI=[IL10]/[IFNγ]=0.53 for influenza samples suggested Th1 immune response. Conclusion. At the early stage of the influenza infection IFNα gene expression activation along with the induction of TNF family cytokines (APRIL and BAFF), their receptors (sTNF-R1 and sTNF-R2) and osteopontin as well as the inhibition of the complex gp130/sIL-6Rβ and metalloprotease ММР-1 were shown. Th1 immune response regulated by IL10 resulted in the recovery of the patients without complications.
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Fedorova, I. M., S. I. Koteleva, I. V. Kapustin, M. S. Blyakher, E. A. Tulskaya, N. N. Zvereva, M. A. Ilina, M. A. Saifullin, A. A. Samkov, and E. V. Vlasov. "Hormone therapy affecting interferon defense in children with infectious mononucleosis." Russian Journal of Infection and Immunity 11, no. 5 (June 28, 2021): 943–50. http://dx.doi.org/10.15789/2220-7619-tsc-1350.
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23 children diagnosed with acute infectious mononucleosis were hospitalized and examined after a short prednisolone treatment course. Related interferon status during infection was compared with that in 38 patients with acute infectious mononucleosis receiving no hormone therapy. Interferon status was investigated by Ershov method, allowing to estimate amount of interferon in the blood serum samples or patient blood cell culture by assessing interferon biological activity. Along with measuring IFNα or IFNγ biological activity, their level was quantified by using enzyme immunoassay. Immunological examination conducted on the next day after the end of hormone therapy revealed sharply decreased potential of patient blood cells to produce both IFNα and IFNγ. The multiplicity of IFNα and IFNγ titer reduction in various patients varied by 4–5 and 3–4-fold, respectively. The concentration of IFNα, determined by ELISA, decreased by 4–6-fold, whereas for IFNγ — by 1.5–2-fold. A follow-up examination 1 month after discharge from the clinic showed that mean IFNα titer in children aged 3–6 years and treated with prednisolone was significantly reduced compared to the baseline, whereas most patients receiving no hormone therapy had normal IFNα production. The change in the level of IFNα 1 month after hormone therapy in 7–14-year age group was similar. IFNγ production quickly recovered, and 1 month after discharge from the clinic, its concentration in culture supernatants from patients reached 10–15 ng/ml, exceeding normal values more than twice. The biological activity of IFNγ in these culture supernatants was significantly higher than those immediately after hormone therapy, whereas in 3–6-year-old group of patients it was also higher than baseline level. These results can serve as a laboratory justification for including recombinant IFNα-2b drugs in the therapy of such patients, presumably immediately after the end of hormone course. Overall, laboratory justified administration of interferon preparations seems to be necessary to determine optimal timepoint for applying such drugs to increase effectiveness for achieving a durable patient recovery.
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Sherwani, Mohammad Asif, Israr Ahmad, Monica J. Lewis, Ahmed Abdelgawad, Harunur Rashid, Kevin Yang, Ching-Yi Chen, Chander Raman, Craig A. Elmets, and Nabiha Yusuf. "Type I Interferons Enhance the Repair of Ultraviolet Radiation-Induced DNA Damage and Regulate Cutaneous Immune Suppression." International Journal of Molecular Sciences 23, no. 3 (February 5, 2022): 1822. http://dx.doi.org/10.3390/ijms23031822.
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Type I interferons (IFNs) are important enhancers of immune responses which are downregulated in human cancers, including skin cancer. Solar ultraviolet (UV) B radiation is a proven environmental carcinogen, and its exposure contributes to the high prevalence of skin cancer. The carcinogenic effects of UV light can be attributed to the formation of cyclobutane pyrimidine dimers (CPD) and errors in the repair and replication of DNA. Treatment with a single dose of UVB (100 mJ/cm2) upregulated IFNα and IFNβ in the skin of C57BL/6 mice. IFNα and IFNβ were predominantly produced by CD11b+ cells. In mice lacking the type I IFN receptor 1 (IFNAR1), the repair of CPD following cutaneous exposure to a single dose of UVB (100 mJ/cm2) was decreased. UVB induced the expression of the DNA repair gene xeroderma pigmentosum A (XPA) in wild-type (WT) mice. In contrast, such treatment in IFNAR1 (IFNAR1-/-) mice downregulated XPA. A local UVB regimen consisting of UVB radiation (150 mJ/cm2) for 4 days followed by sensitization with hapten 2,4, dinitrofluorobenzene (DNFB) resulted in significant suppression of immune responses in both WT and IFNAR1-/- mice. However, there were significantly higher CD4+CD25+Foxp3+ regulatory T-cells in the draining lymph nodes of IFNAR1-/- mice in comparison to WT mice. Overall, our studies reveal a previously unknown action of type I IFNs in the repair of photodamage and the prevention of UVB-induced immune suppression.
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Coto-Llerena, Mairene, Marco Lepore, Julian Spagnuolo, Daniela Di Blasi, Diego Calabrese, Aleksei Suslov, Glenn Bantug, et al. "Interferon lambda 4 can directly activate human CD19+ B cells and CD8+ T cells." Life Science Alliance 4, no. 1 (November 6, 2020): e201900612. http://dx.doi.org/10.26508/lsa.201900612.
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Compared with the ubiquitous expression of type I (IFNα and IFNβ) interferon receptors, type III (IFNλ) interferon receptors are mainly expressed in epithelial cells of mucosal barriers of the of the intestine and respiratory tract. Consequently, IFNλs are important for innate pathogen defense in the lung and intestine. IFNλs also determine the outcome of hepatitis C virus (HCV) infections, with IFNλ4 inhibiting spontaneous clearance of HCV. Because viral clearance is dependent on T cells, we explored if IFNλs can directly bind to and regulate human T cells. We found that human B cells and CD8+ T cells express the IFNλ receptor and respond to IFNλs, including IFNλ4. IFNλs were not inhibitors but weak stimulators of B- and T-cell responses. Furthermore, IFNλ4 showed neither synergistic nor antagonistic effects in co-stimulatory experiments with IFNλ1 or IFNα. Multidimensional flow cytometry of cells from liver biopsies of hepatitis patients from IFNλ4-producers showed accumulation of activated CD8+ T cells with a central memory-like phenotype. In contrast, CD8+ T cells with a senescent/exhausted phenotype were more abundant in IFNλ4–non-producers. It remains to be elucidated how IFNλ4 promotes CD8 T-cell responses and inhibits the host immunity to HCV infections.
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Vasuthasawat, Alex, Reiko E. Yamada, Kham R. Trinh, Neiki Rokni, Sherie L. Morrison, and John M. Timmerman. "In Vivo Efficacy of Anti-CD20-Interferon-Gamma Fusion Protein Against Syngeneic B Cell Lymphoma Is Mediated By Natural Killer Cells." Blood 134, Supplement_1 (November 13, 2019): 1575. http://dx.doi.org/10.1182/blood-2019-131890.
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Background: The interferons, including IFNα/IFNβ (type I) and IFNγ (type II) are essential mediators of anti-cancer immunity. To achieve efficient targeting of IFNs to tumor sites, we have developed antibody (Ab)-IFN fusion protein technology. We previously reported the antigen-specific targeting of IFNα to CD20+ target cells with efficient inhibition of proliferation, induction of apoptosis, and in vivo tumor eradiation dependent upon IFNα receptors on the tumor cell surface (Xuan et al, Blood, 2010). A fusion protein targeting human CD20 (anti-CD20-IFNα) exhibited stronger direct anti-proliferative effects, complement-dependent cytotoxicity (CDC), Ab-dependent cell-mediated cytotoxicity (ADCC), and in vivo potency against B-cell lymphoma xenograft models compared to the parent Ab rituximab (Timmerman et al, Blood 2015). Based on these results, a phase I, first-in-human, dose-escalation trial of anti-CD20-IFNα for B cell non-Hodgkin lymphoma is now underway (NCT02519270). Given the distinct properties of IFNγ from type I IFNs, including upregulation of antigen presentation, control of immune cell trafficking, and activation of T cells, NK cells, and macrophages, we hypothesized that Ab-targeted IFNγ may have anti-tumor effects mechanistically-distinct from those of Ab-IFNα fusions. We now report on the construction and characterization of anti-CD20 fusions containing IFNγ. Methods: The VH and VL regions from antibody 2B8 recognizing human CD20 were engineered in recombinant form with mouse IgG2a constant regions, and fused at the C-terminus with mIFNγ, yielding anti-hCD20-mIFNγ. Tumor cell proliferation in vitro was measured by [3H]-thymidine incorporation, ADCC by LDH release using mouse splenocyte effectors, CDC by propidium iodide (PI) exclusion, and in vivo tumor growth assessed using the huCD20-expressing syngeneic mouse B cell lymphoma 38C13-huCD20. Tumor-infiltrating lymphocytes were measured by flow cytometry. Results: Anti-hCD20-mIFNγ displayed potent IFNγ bioactivity comparable to free recombinant mIFNγ, and suppressed the in vitro proliferation of 38C13-huCD20 lymphoma cells by up to 70% (at 1 nM), though not as potently as anti-hCD20-mIFNα, which inhibited proliferation by 98% (Figure 1). Anti-hCD20-mIFNγ showed enhanced ADCC against lymphoma cells compared with the unfused, parent antibody (16-20% at E:T ratio of 20:1, versus 9-12%, respectively, p=0.0024)(Figure 2), while CDC was identical to unfused antibody. In vivo efficacy was demonstrated in mice bearing established subcutaneous 38C13-huCD20 tumors, with systemic (i.v.) injection of 100 μg anti-hCD20-mIFNγ fusion protein on days 5, 6, 7, or 5, 6, 7, 9 after tumor inoculation resulting in cure of approximately 70-80% of mice in repeated experiments. In contrast, therapy with equimolar doses of unfused, native anti-hCD20 Ab resulted in no cures. Mechanistic studies in anti-hCD20-mIFNγ fusion protein-treated mice showed that depletion of natural killer (NK) cells (using anti-asialo-GM1) significantly abrogated tumor clearance (p=0.01), while depletion of macrophages (clodronate liposomes) had lesser, borderline effects (p= 0.05)(Figure 2), and depletion of complement (cobra venom factor) or T cells (CD4+ or CD8+) had no significant effects on tumor eradication. Subcutaneous mouse B cell lymphomas treated with intratumoral injections of anti-hCD20-mIFNγ displayed increased tumor-infiltrating CD8+ T cells (mean 20.6% versus 5% in PBS-treated controls, p=0.008), and CD4+ T cells (mean 15.3% versus 6.6%). Conclusions: Anti-hCD20-mIFNγ fusion protein has in vitro and in vivo efficacy in a syngeneic, immunocompetent model of B cell lymphoma, with NK cells and possibly macrophages implicated in the mechanism(s) of tumor eradication. Ab-targeted mIFNγ can also promote infiltration of immune cells into the tumor microenvironment. These findings may suggest a novel approach for the immunotherapy of B cell lymphomas and other cancers. Disclosures Vasuthasawat: Qwixel therapeutics LLC: Other: stake;which receives some funding through UCLA. Trinh:Qwixel therapeutics LLC: Other: stake;which receives some funding through UCLA. Morrison:Qwixel therapeutics LLC: Other: stake;which receives some funding through UCLA. Timmerman:ImmunGene: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: travel support, Research Funding; Merck: Research Funding; Kite, A Gilead Company: Consultancy, Honoraria, Other: travel support, Research Funding; Spectrum Pharmaceuticals: Research Funding.
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Werner, Melanie, Stefan Schefczyk, Martin Trippler, Juergen W. Treckmann, Hideo A. Baba, Guido Gerken, Joerg F. Schlaak, and Ruth Broering. "Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3." Viruses 14, no. 2 (January 24, 2022): 218. http://dx.doi.org/10.3390/v14020218.
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The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tumor resections or liver transplantations. Cells were stimulated with Toll-like receptor 1–9 ligands for 6–24 h. Non-parenchymal liver cells expressed and secreted inflammatory cytokines (IL6, TNF and IL10). Toll-like receptor- and cell type-specific downstream signals included the phosphorylation of NF-κB, AKT, JNK, p38 and ERK1/2. However, only supernatants of TLR3-activated Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells contained type I and type III interferons and mediated an antiviral activity in the interferon-sensitive subgenomic hepatitis C virus replicon system. The antiviral effect could not be neutralized by antibodies against IFNA, IFNB nor IFNL, but could be abrogated using an interferon alpha receptor 2-specific neutralization. Interestingly, TLR3 responsiveness was enhanced in liver sinusoidal endothelial cells isolated from hepatitis C virus-positive donors, compared to uninfected controls. In conclusion, non-parenchymal liver cells are potent activators of the hepatic immune system by mediating inflammatory responses. Furthermore, liver sinusoidal endothelial cells were identified to be hyperresponsive to viral stimuli in chronic hepatitis C virus infection.
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Vlasáková, Jana, Zora Nováková, Lenka Rossmeislová, Michal Kahle, Pavel Hozák, and Zdenĕk Hodný. "Histone deacetylase inhibitors suppress IFNα-induced up-regulation of promyelocytic leukemia protein." Blood 109, no. 4 (October 24, 2006): 1373–80. http://dx.doi.org/10.1182/blood-2006-02-003418.
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Abstract Promyelocytic leukemia nuclear bodies (PML NBs), the structural domains of the eukaryotic cell nucleus, play a role in cancer and apoptosis, and their involvement in antiviral mechanisms mediated by interferons (IFNs) is proposed. IFNs dramatically increase the transcription of the PML gene. In this study, we have shown that the response of 2 structural PML NB components, PML and Sp100, to interferon-α (IFNα) was suppressed in cells simultaneously treated with histone deacetylase (HDAC) inhibitors (trichostatin A, sodium butyrate, MS-275, SAHA, and valproic acid). Trichostatin A (TSA) blocked the increase of PML NB number and suppressed up-regulation of PML mRNA and protein levels in several human cell lines and in normal diploid skin fibroblasts. Moreover, IFNα induction of IRF-1 was also inhibited by TSA, although incompletely. Analysis of cellular fractions did not show any defects in cytoplasmic-nuclear transport of STAT2, a component of transcription factor ISGF3 responsible for IFNα/β-dependent gene transcription. Moreover, chromatin immunoprecipitation showed that after IFNα stimulation STAT2 binds to ISRE element of PML promoter even in the presence of TSA and thus excluded STAT2-dependent mechanism of TSA effect. These results indicate that the action of histone deacetylases is necessary for the full transcriptional activation of IFNα-stimulated genes.
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Barba, Cindy, H. Atakan Ekiz, William Weihao Tang, Arevik Ghazaryan, Mason Hansen, Soh-Hyun Lee, Warren Peter Voth, and Ryan Michael O’Connell. "Interferon Gamma-Inducible NAMPT in Melanoma Cells Serves as a Mechanism of Resistance to Enhance Tumor Growth." Cancers 15, no. 5 (February 23, 2023): 1411. http://dx.doi.org/10.3390/cancers15051411.
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(1) Background: Immune cells infiltrate the tumor microenvironment and secrete inflammatory cytokines, including interferons (IFNs), to drive antitumor responses and promote tumor clearance. However, recent evidence suggests that sometimes, tumor cells can also harness IFNs to enhance growth and survival. The essential NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) gene is constitutively expressed in cells during normal homeostasis. However, melanoma cells have higher energetic demands and elevated NAMPT expression. We hypothesized that interferon gamma (IFNγ) regulates NAMPT in tumor cells as a mechanism of resistance that impedes the normal anti-tumorigenic effects of IFNγ. (2) Methods: Utilizing a variety of melanoma cells, mouse models, Crispr-Cas9, and molecular biology techniques, we explored the importance of IFNγ-inducible NAMPT during melanoma growth. (3) Results: We demonstrated that IFNγ mediates the metabolic reprogramming of melanoma cells by inducing Nampt through a Stat1 binding site in the Nampt gene, increasing cell proliferation and survival. Further, IFN/STAT1-inducible Nampt promotes melanoma in vivo. (4) Conclusions: We provided evidence that melanoma cells directly respond to IFNγ by increasing NAMPT levels, improving their fitness and growth in vivo (control n = 36, SBS KO n = 46). This discovery unveils a possible therapeutic target that may improve the efficacy of immunotherapies involving IFN responses in the clinic.
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Shemesh, Maya, Turgut E. Aktepe, Joshua M. Deerain, Julie L. McAuley, Michelle D. Audsley, Cassandra T. David, Damian F. J. Purcell, et al. "SARS-CoV-2 suppresses IFNβ production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon." PLOS Pathogens 17, no. 8 (August 26, 2021): e1009800. http://dx.doi.org/10.1371/journal.ppat.1009800.
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Type I Interferons (IFN-Is) are a family of cytokines which play a major role in inhibiting viral infection. Resultantly, many viruses have evolved mechanisms in which to evade the IFN-I response. Here we tested the impact of expression of 27 different SARS-CoV-2 genes in relation to their effect on IFN production and activity using three independent experimental methods. We identified six gene products; NSP6, ORF6, ORF7b, NSP1, NSP5 and NSP15, which strongly (>10-fold) blocked MAVS-induced (but not TRIF-induced) IFNβ production. Expression of the first three of these SARS-CoV-2 genes specifically blocked MAVS-induced IFNβ-promoter activity, whereas all six genes induced a collapse in IFNβ mRNA levels, corresponding with suppressed IFNβ protein secretion. Five of these six genes furthermore suppressed MAVS-induced activation of IFNλs, however with no effect on IFNα or IFNγ production. In sharp contrast, SARS-CoV-2 infected cells remained extremely sensitive to anti-viral activity exerted by added IFN-Is. None of the SARS-CoV-2 genes were able to block IFN-I signaling, as demonstrated by robust activation of Interferon Stimulated Genes (ISGs) by added interferon. This, despite the reduced levels of STAT1 and phospho-STAT1, was likely caused by broad translation inhibition mediated by NSP1. Finally, we found that a truncated ORF7b variant that has arisen from a mutant SARS-CoV-2 strain harboring a 382-nucleotide deletion associating with mild disease (Δ382 strain identified in Singapore & Taiwan in 2020) lost its ability to suppress type I and type III IFN production. In summary, our findings support a multi-gene process in which SARS-CoV-2 blocks IFN-production, with ORF7b as a major player, presumably facilitating evasion of host detection during early infection. However, SARS-CoV-2 fails to suppress IFN-I signaling thus providing an opportunity to exploit IFN-Is as potential therapeutic antiviral drugs.
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Mattila, Joshua T., Priyanka Talukdar, and Beth A. Junecko. "Type 3 interferons expressed in tuberculous granulomas may influence signaling in epithelioid macrophages." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 117.25. http://dx.doi.org/10.4049/jimmunol.200.supp.117.25.
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Abstract Type 3 interferons, also known as interferon lambda (IFNλ), play important roles in mucosal immunity and protection against viral infection, but their roles in tuberculosis (TB) remain to be investigated. IFNλ have properties that partially overlap with type 1 interferons (IFNα/β), a group of cytokines whose expression positively correlates with TB severity. Conversely, IFNλ can downregulate neutrophilic inflammation, and because neutrophils can be pathologic in TB, IFNλ may have currently-unappreciated protective effects. To better understand IFNλ expression in tuberculous lung granulomas, we performed RT-PCR analysis and immunohistochemistry on cynomolgus macaques with TB, a nonhuman primate with human-like pathology, to determine whether IFNλ is expressed in granulomas and to identify IFNλ-expressing cells at the site of disease. We found that mRNAs for the IFNλ isoforms IFNλ1 (IL-29), IFNλ3 (IL-28B), and IFNλ4 were expressed in normal lung tissue and granulomas, and there was a significant amount of heterogeneity in granuloma IFNλ expression. In normal lung tissue, IFNλ protein expression was most pronounced in ciliated epithelial cells, but there were differences in subcellular localization between isoforms. We identified differences in the subcellular localization of IFNλ4 in different granuloma macrophage subsets, with IFNλ4 in lymphocyte cuff-region macrophages present in the macrophage cytoplasm while in epithelioid macrophages, IFNλ4 was most abundant inside the macrophage nuclei. These data suggest that IFNλ4 may be differentially-expressed by granulomas macrophage subsets and have a previously-unappreciated signaling role in epithelioid macrophages.
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Marijanovic, Zrinka, Josiane Ragimbeau, José van der Heyden, Gilles Uzé, and Sandra Pellegrini. "Comparable potency of IFNα2 and IFNβ on immediate JAK/STAT activation but differential down-regulation of IFNAR2." Biochemical Journal 407, no. 1 (September 12, 2007): 141–51. http://dx.doi.org/10.1042/bj20070605.
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Type I IFNs (interferons) (IFNα/β) form a family of related cytokines that control a variety of cellular functions through binding to a receptor composed of IFNAR (IFNα receptor subunit) 1 and 2. Among type I IFNs, the α2 and β subtypes exhibit a large difference in their binding affinities to IFNAR1, and it was suggested that high concentrations of IFNAR1 may compensate for its low intrinsic binding affinity for IFNα2. We tested whether receptor-proximal signalling events are sensitive to IFNAR1 surface concentration by investigating the relationship between relative IFNAR1/IFNAR2 surface levels and IFNα2 and IFNβ signalling potencies in several cell lines. For this, we monitored the activation profile of JAK (Janus kinase)/STAT (signal transducer and activator of transcription) proteins, measured basal and ligand-induced surface decay of each receptor subunit and tested the effect of variable IFNAR1 levels on IFNα2 signalling potency. Our data show that the cell-surface IFNAR1 level is indeed a limiting factor for assembly of the functional complex, but an increased concentration of it does not translate into an IFNα/β differential JAK/STAT signalling nor does it change the dynamics of the engaged receptor. Importantly, however, our data highlight a differential effect upon routing of IFNAR2. Following binding of IFNα2, IFNAR2 is internalized, but, instead of being routed towards degradation as it is when complexed to IFNβ, it recycles back to the cell surface. These observations suggest strongly that the stability and the intracellular lifetime of the ternary complex account for the differential control of IFNAR2. Moreover, the present study opens up the attractive possibility that endosomal-initiated signalling may contribute to IFNα/β differential bioactivities.
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Premenko-Lanier, Mary. "The in vivo antiviral state is dependent on IFNγ (170.5)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 170.5. http://dx.doi.org/10.4049/jimmunol.188.supp.170.5.
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Abstract Since the discovery of interferons 50 years ago their potential therapeutic use has been a source of active research. Thus far, the most successful interferon therapy has been use of IFNα2 in combination with Ribavirin to treat Hepatitis C (HCV). The success rate for this therapy is only about a 50%. A recent case study showed that adding IFNγ to the standard IFNα/Ribavirin therapy regimen led to clearance of HCV in a patient that had failed the standard therapy. The idea that IFNγ is important for successful therapy against HCV is supported by several in vitro and in vivo studies. Using the well-established mouse model of chronic viral infection, LCMV, we have found that the natural in vivo antiviral state is dependent on interferon gamma (IFNγ). In our whole-organism model early production of IFNγ by CD8+ cells within days of a primary LCMV infection creates an antiviral environment capable of preventing secondary viral infections, whereas IFN-I signaling is surprisingly dispensable. The clearance of the secondary infection is not antigen specific since an acquired immune response to the second infection is not induced. Further, this block is transient and the mice eventually become susceptible to the secondary infection. Finally, the IFNγ induced antiviral state is effective regardless of the route of secondary viral entry. Therefore, a naturally induced sustained antiviral state is dependent on IFNγ production.
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Marchisone, C., R. Benelli, A. Albini, L. Santi, and D. M. Noonan. "Inhibition of Angiogenesis by Type I Interferons in Models of Kaposi'S Sarcoma." International Journal of Biological Markers 14, no. 4 (October 1999): 257–62. http://dx.doi.org/10.1177/172460089901400411.
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Kaposi's Sarcoma (KS) is a pathology which occurs with increased frequency and in a particularly aggressive form in AIDS patients. The HIV-1 Tat protein appears to be an important co-factor in the induction of the extensive neo-vascularization associated with AIDS-KS. Tat acts as a chemoattractant for endothelial cells in vitro, inducing both chemotactic and invasive responses. Several clinical trials have been performed testing the effectiveness of diverse biological agents in therapy of KS, among these the type I interferons. Type I IFNs have diverse biological functions besides their anti-viral activity, including anti-angiogenic properties. We have shown that IFNα and IFNβ are potent inhibitors of both primary and immortalized endothelial cell migration and morphogenesis in vitro as well as neo-angiogenesis induced by HIV-1 Tat in vivo. The inhibitory effect of IFN class I on HIV-Tat associated angiogenesis further supports its use as a therapy for epidemic Kaposi's sarcoma. The use of recombinant IFNs at the levels required to obtain a therapeutic effect are associated with side effects and toxicity, therefore we are now developing a gene therapy approach for constant and local delivery type I IFNs.
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Kathamuthu, Gokul Raj, Kadar Moideen, Rathinam Sridhar, Dhanaraj Baskaran, and Subash Babu. "Systemic Levels of Pro-Inflammatory Cytokines and Post-Treatment Modulation in Tuberculous Lymphadenitis." Tropical Medicine and Infectious Disease 8, no. 3 (February 27, 2023): 150. http://dx.doi.org/10.3390/tropicalmed8030150.
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Pro-inflammatory cytokines are potent stimulators of inflammation and immunity and markers of infection severity and bacteriological burden in pulmonary tuberculosis (PTB). Interferons could have both host-protective and detrimental effects on tuberculosis disease. However, their role has not been studied in tuberculous lymphadenitis (TBL). Thus, we evaluated the systemic pro-inflammatory (interleukin (IL)-12, IL-23, interferon (IFN)α, and IFNβ) cytokine levels in TBL, latent tuberculosis (LTBI), and healthy control (HC) individuals. In addition, we also measured the baseline (BL) and post-treatment (PT) systemic levels in TBL individuals. We demonstrate that TBL individuals are characterized by increased pro-inflammatory (IL-12, IL-23, IFNα, IFNβ) cytokines when compared to LTBI and HC individuals. We also show that after anti-tuberculosis treatment (ATT) completion, the systemic levels of pro-inflammatory cytokines were significantly modulated in TBL individuals. A receiver operating characteristic (ROC) analysis revealed IL-23, IFNα, and IFNβ significantly discriminated TBL disease from LTBI and/or HC individuals. Hence, our study demonstrates the altered systemic levels of pro-inflammatory cytokines and their reversal after ATT, suggesting that they are markers of disease pathogenesis/severity and altered immune regulation in TBL disease.
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Marrero, Bernadette, Yin Liu, Yan Huang, Adriana Almeida De Jesus, and Raphaela Goldbach-Mansky. "Comparative studies connecting IFN dysregulation with pathway dysregulation in 2 autoinflammatory diseases, SAVI and CANDLE (HUM1P.274)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 52.23. http://dx.doi.org/10.4049/jimmunol.194.supp.52.23.
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Abstract Type I interferon dysregulation is associated with some autoinflammatory diseases. Gain-of-function mutations in TMEM173 encoding Stimulator of Interferon Genes (STING) lead to constitutive production of Type I IFN and the clinical syndrome, STING associated vasculopathy with onset in infancy (SAVI). In another IFN mediated disease, Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature (CANDLE), disease causing mutations cause global proteasome dysfunction and increase in IFN message. The cellular source of the IFNs in blood and the dominant isoforms remain unclear. We examined the expression of 5 type I IFN genes among FACS sorted PBMCs: T-, B-, NK cells and monocytes in SAVI (n=2) and total PBMCs from CANDLE patients (n=2) by qRTPCR. We found in SAVI that monocytes expressed the highest level of type I IFN message. Among the IFN genes tested and normalized to healthy monocytes, patients’ IFNβ is over 250-fold higher than IFNα; following the notion that STING pathway activation leads to IFNβ transcription. Depleting monocytes from SAVI PBMCs reduced 90% of the IFN message, confirming that monocytes not dendritic cells are the main source of IFNs. In contrast, CANDLE patients’ IFN alpha and beta genes are comparably upregulated. Although IFN dysregulation is identified in blood, determining the cellular origin of the IFN production and the pathways that drive IFN dysregulation will allow us to develop better targets for therapy.
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Bruening, Janina, Bettina Weigel, and Gisa Gerold. "The Role of Type III Interferons in Hepatitis C Virus Infection and Therapy." Journal of Immunology Research 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/7232361.
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The human interferon (IFN) response is a key innate immune mechanism to fight virus infection. IFNs are host-encoded secreted proteins, which induce IFN-stimulated genes (ISGs) with antiviral properties. Among the three classes of IFNs, type III IFNs, also called IFN lambdas (IFNLs), are an essential component of the innate immune response to hepatitis C virus (HCV). In particular, human polymorphisms in IFNL gene loci correlate with hepatitis C disease progression and with treatment response. To date, the underlying mechanisms remain mostly elusive; however it seems clear that viral infection of the liver induces IFNL responses. As IFNL receptors show a more restricted tissue expression than receptors for other classes of IFNs, IFNL treatment has reduced side effects compared to the classical type I IFN treatment. In HCV therapy, however, IFNL will likely not play an important role as highly effective direct acting antivirals (DAA) exist. Here, we will review our current knowledge on IFNL gene expression, protein properties, signaling, ISG induction, and its implications on HCV infection and treatment. Finally, we will discuss the lessons learnt from the HCV and IFNL field for virus infections beyond hepatitis C.
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Pinal-Fernandez, Iago, Maria Casal-Dominguez, Assia Derfoul, Katherine Pak, Paul Plotz, Frederick W. Miller, Jose C. Milisenda, et al. "Identification of distinctive interferon gene signatures in different types of myositis." Neurology 93, no. 12 (August 21, 2019): e1193-e1204. http://dx.doi.org/10.1212/wnl.0000000000008128.
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ObjectiveActivation of the type 1 interferon (IFN1) pathway is a prominent feature of dermatomyositis (DM) muscle and may play a role in the pathogenesis of this disease. However, the relevance of the IFN1 pathway in patients with other types of myositis such as the antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM) is largely unknown. Moreover, the activation of the type 2 interferon (IFN2) pathway has not been comprehensively explored in myositis. In this cross-sectional study, our objective was to determine whether IFN1 and IFN2 pathways are differentially activated in different types of myositis by performing RNA sequencing on muscle biopsy samples from 119 patients with DM, IMNM, AS, or IBM and on 20 normal muscle biopsies.MethodsThe expression of IFN1- and IFN2-inducible genes was compared between the different groups.ResultsThe expression of IFN1-inducible genes was high in DM, moderate in AS, and low in IMNM and IBM. In contrast, the expression of IFN2-inducible genes was high in DM, IBM, and AS but low in IMNM. The expression of IFN-inducible genes correlated with the expression of genes associated with inflammation and muscle regeneration. Of note, ISG15 expression levels alone performed as well as composite scores relying on multiple genes to monitor activation of the IFN1 pathway in myositis muscle biopsies.ConclusionsIFN1 and IFN2 pathways are differentially activated in different forms of myositis. This observation may have therapeutic implications because immunosuppressive medications may preferentially target each of these pathways.
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Rigolet, Muriel, Cyrielle Hou, Yasmine Baba Amer, Jessie Aouizerate, Baptiste Periou, Romain K. Gherardi, Peggy Lafuste, and François Jérôme Authier. "Distinct interferon signatures stratify inflammatory and dysimmune myopathies." RMD Open 5, no. 1 (February 2019): e000811. http://dx.doi.org/10.1136/rmdopen-2018-000811.
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ObjectiveThe role of interferons (IFN) in the pathophysiology of primary inflammatory and dysimmune myopathies (IDM) is increasingly investigated, notably because specific neutralisation approaches may constitute promising therapeutic tracks. In present work we analysed the muscular expression of specific IFNα/β and IFNγ-stimulated genes in patients with various types of IDM.Methods39 patients with IDM with inclusion body myositis (IBM, n=9), dermatomyositis (DM, n=10), necrotising autoimmune myopathies (NAM, n=10) and antisynthetase myositis (ASM, n=10), and 10 controls were included. Quantification of expression levels of IFNγ, ISG15, an IFNα/β-inducible gene and of six IFNγ-inducible genes (GBP2, HLA-DOB, HLA-DPB, CIITA, HLA-DRB and HLA-DMB) was performed on muscle biopsy samples.ResultsDM usually associated with strong type I IFNα/β signature, IBM and ASM with prominent type II IFNγ signature and NAM with neither type I nor type II IFN signature. Immunofluorescence study in ASM and IBM showed myofibre expression of major histocompatibility class 2 (MHC-2) and CIITA, confirming the induction of the IFNγ pathway. Furthermore, MHC-2-positive myofibres were observed in close proximity to CD8+ T cells which produce high levels of IFNγ.ConclusionDistinct IFN signatures allow a more distinct segregation of IDMs and myofibre MHC-2 expression is a reliable biomarker of type II IFN signature.
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Tanaka, A., T. Ito, K. Kibata, N. Inagaki-Katashiba, H. Amuro, T. Nishizawa, Y. Son, Y. Ozaki, and S. Nomura. "Serum high-mobility group box 1 is correlated with interferon-α and may predict disease activity in patients with systemic lupus erythematosus." Lupus 28, no. 9 (July 12, 2019): 1120–27. http://dx.doi.org/10.1177/0961203319862865.
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Sensing self-nucleic acids through toll-like receptors in plasmacytoid dendritic cells (pDCs), and the dysregulated type I IFN production, represent pathogenic events in the development of the autoimmune responses in systemic lupus erythematosus (SLE). Production of high-mobility group box-1 protein (HMGB1) promotes type I IFN response in pDCs. To better understand the active pathogenic mechanism of SLE, we measured serum levels of HMGB1, thrombomodulin, and cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17A, IL-17F, IFNα, IFNγ, TNFα) in 35 patients with SLE. Serum HMGB1 and IFNα were significantly higher in patients with active SLE (SLE Disease Activity Index (SLEDAI) score ≥ 6) compared with healthy donors or patients with inactive SLE. Furthermore, the HMGB1 levels were significantly correlated with IFNα levels. By qualitative analysis, the detection of serum IFNα or HMGB1 suggests active SLE and the presence of SLE-related arthritis, fever, and urinary abnormality out of SLEDAI manifestations. Collectively, HMGB1 and IFNα levels are biomarkers reflecting disease activity, and qualitative analysis of IFNα or HMGB1 is a useful screening test to estimate SLE severity and manifestations. Our results suggest the clinical significance of type I IFNs and HMGB1 as key molecules promoting the autoimmune process in SLE.
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Fischer, Matthew, Luo Jia, and Karen Edelblum. "T cell receptor signaling mediates enhanced IFNγ production by γδ intraepithelial lymphocytes in response to type I interferon." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 150.19. http://dx.doi.org/10.4049/jimmunol.210.supp.150.19.
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Abstract Intraepithelial lymphocytes (IEL) expressing the γδ T cell receptor (TCR) provide a rapid response to limit enteric pathogen invasion. Despite constant γδTCR triggering in vivo, these IELs remain immunologically quiescent until their activation threshold is surpassed. Activated γδ IELs limit viral replication by producing type I interferons (IFN), such as IFNα, yet the extent to which IFNα activates γδ IELs remains unknown. To this end, murine small intestinal γδ IELs were stimulated ex vivowith 1 ug/mL αCD3, 10 ng/mL IFNα or both for 5 h. We observed a 26%±10 increase in IFNγ +γδ IELs treated with αCD3 and IFNα compared to αCD3 treatment alone (p<0.0001) and a 2-fold increase in IFNγ MFI (p<0.0001). Using Nur77-GFP mice, we found that only Nur77 +γδ IELs produced IFNγ (p<0.0001), indicating that TCR signaling is necessary for IFNα-induced effector function. Suboptimal αCD3 stimulation (0.1 ug/mL) was sufficient to increase the frequency of IFNγ +γδ IELs following IFNα exposure relative to αCD3 alone (p<0.001). To interrogate the molecular mechanism involved in IFNα co-stimulation, γδ IELs were treated with PMA and/or ionomycin in the presence or absence of IFNα. Ionomycin and IFNα increased the frequency of IFNγ +γδ IELs by 16%±7 compared to ionomycin alone (p<0.0001), whereas PMA had no effect. Pharmacological inhibition of NFAT signaling (10 uM INCA6) abrogated both TCR- or IFNα-induced γδ IEL IFNγ production (p<0.01 or p<0.0001, respectively). Lastly, we observed that the co-stimulatory effect of IFNα was lost in STAT4-deficient γδ IELs compared to WT (p<0.0001). Together, these data indicate that low level TCR signaling through NFAT is required for IFNα to rapidly enhance γδ IEL IFNγ production in a STAT4-dependent manner. This work was supported by the National Institutes of Health R01 DK119349, the New Jersey Commission on Cancer Research, Busch Biomedical Research grant and the RBHS Chancellor Scholar Award (KLE).
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Yu, Dehai, Zhonghua Du, Wei Li, Huaqiu Chen, Songgen Ye, Andrew R. Hoffman, Jiuwei Cui, and Ji-Fan Hu. "Targeting Jurkat T Lymphocyte Leukemia Cells by an Engineered Interferon-Alpha Hybrid Molecule." Cellular Physiology and Biochemistry 42, no. 2 (2017): 519–29. http://dx.doi.org/10.1159/000477601.
Full textAbstract:
Background/Aims: Adult T-cell leukemia/lymphoma (ATL) is a very aggressive T cell malignancy that carries a poor prognosis, primarily due to its resistance to chemotherapy and to life-threatening infectious complications. Interferon-alpha (IFNα) has been used in combination with the anti-retroviral drug zidovudine to treat patients with ATL. However, the efficacy of long-term therapy is significantly limited due to the systemic toxicity of IFNα. Methods: We utilized phage display library screening to identify short peptides that specifically bind to Jurkat T lymphocyte leukemia cells. By fusing the Jurkat-binding peptide to the C-terminus of IFNα, we constructed an engineered chimeric IFNα molecule (IFNP) for the treatment of ATL. Results: We found that IFNP exhibited significantly higher activity than wild type IFNα in inhibiting the growth of leukemia cells and inducing cell blockage at the G0/G1 phase. The synthetic IFNP molecule exerted its antitumor activity by upregulating the downstream genes involved in the STAT1 pathway and in apoptosis. Using a cell receptor binding assay, we showed that this Jurkat-binding peptide facilitated the binding affinity of IFNα to the cell surface type I IFN receptor. Conclusion: The isolated Jurkat-binding peptide significantly potentiates the therapeutic activity of IFNα in T lymphocyte leukemia cells. The engineered IFNP molecule may prove to a novel antitumor approach in the treatment of patients with ATL.