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• W2014906922 abstract "Environmental factors, such as viral infection, have been implicated as potential triggering events leading to the initial destruction of pancreatic β cells during the development of autoimmune diabetes. Double-stranded RNA (dsRNA), the active component of a viral infection that stimulates antiviral responses in infected cells, has been shown in combination with interferon-γ (IFN-γ) to stimulate inducible nitric oxide synthase (iNOS) expression and nitric oxide production and to inhibit β cell function. Interferon regulatory factor-1 (IRF-1), the activation of which is induced by dsRNA, viral infection, and IFN-γ, regulates the expression of many antiviral proteins, including PKR, type I IFN, and iNOS. In this study, we show that IRF-1 is not required for dsRNA + IFN-γ-stimulated iNOS expression and nitric oxide production by mouse islets. In contrast to islets, dsRNA + IFN-γ fails to induce iNOS expression or nitric oxide production by macrophages isolated from IRF-1−/− mice; however, dsRNA + IFN-γ induces similar levels of IL-1 release by macrophages isolated from both IRF-1−/− and IRF-1+/+ mice. Importantly, we show that dsRNA- or dsRNA + IFN-γ-stimulated IRF-1 expression by mouse islets and peritoneal macrophages is independent of PKR. These results indicate that IRF-1 is required for dsRNA + IFN-γ-induced iNOS expression and nitric oxide production by mouse peritoneal macrophages but not by mouse islets. These findings suggest that dsRNA + IFN-γ stimulates iNOS expression by two distinct PKR-independent mechanisms; one that is IRF-1-dependent in macrophages and another that is IRF-1-independent in islets. Environmental factors, such as viral infection, have been implicated as potential triggering events leading to the initial destruction of pancreatic β cells during the development of autoimmune diabetes. Double-stranded RNA (dsRNA), the active component of a viral infection that stimulates antiviral responses in infected cells, has been shown in combination with interferon-γ (IFN-γ) to stimulate inducible nitric oxide synthase (iNOS) expression and nitric oxide production and to inhibit β cell function. Interferon regulatory factor-1 (IRF-1), the activation of which is induced by dsRNA, viral infection, and IFN-γ, regulates the expression of many antiviral proteins, including PKR, type I IFN, and iNOS. In this study, we show that IRF-1 is not required for dsRNA + IFN-γ-stimulated iNOS expression and nitric oxide production by mouse islets. In contrast to islets, dsRNA + IFN-γ fails to induce iNOS expression or nitric oxide production by macrophages isolated from IRF-1−/− mice; however, dsRNA + IFN-γ induces similar levels of IL-1 release by macrophages isolated from both IRF-1−/− and IRF-1+/+ mice. Importantly, we show that dsRNA- or dsRNA + IFN-γ-stimulated IRF-1 expression by mouse islets and peritoneal macrophages is independent of PKR. These results indicate that IRF-1 is required for dsRNA + IFN-γ-induced iNOS expression and nitric oxide production by mouse peritoneal macrophages but not by mouse islets. These findings suggest that dsRNA + IFN-γ stimulates iNOS expression by two distinct PKR-independent mechanisms; one that is IRF-1-dependent in macrophages and another that is IRF-1-independent in islets. interleukin-1 double-stranded RNA interferon inducible nitric oxide synthase polyinosinic-polycytidylic acid interferon regulatory factor-1 tumor necrosis factor lipopolysaccharide nuclear factor signal transducers and activators of transcription glyceraldehyde-3-phosphate dehydrogenase polymerase chain reaction reverse transcription Autoimmune diabetes is characterized by a local inflammatory reaction in and around the pancreatic islets of Langerhans, followed by selective destruction of insulin-producing β cells (1Gepts W. Diabetes. 1965; 14: 619-633Crossref PubMed Scopus (969) Google Scholar, 2Sibley R.K. Sutherland D.E. Goetz F. Michael A.F. Lab. Invest. 1985; 53: 132-144PubMed Google Scholar). This inflammatory reaction consists of macrophages, monocytes, T and B lymphocytes, and natural killer cells that infiltrate into the islet after an initial triggering event to cause β cell destruction (2Sibley R.K. Sutherland D.E. Goetz F. Michael A.F. Lab. Invest. 1985; 53: 132-144PubMed Google Scholar, 3Lee K.U. Amano K. Yoon J.W. Diabetes. 1988; 37: 989-991Crossref PubMed Scopus (221) Google Scholar). Although the mechanism associated with the autoimmune reaction leading to the development of diabetes has been studied in detail, few studies have examined the precipitating events that trigger the initial destruction of β cells leading to this autoimmune inflammatory reaction. We and others have shown that IL-11 induces an inhibition of insulin secretion and the subsequent destruction of rat islets that is mediated by the local production of nitric oxide by β cells (4Mandrup-Poulsen T. Bendtzen K. Nielsen J.H. Bendixen G. Nerup J. Allergy. 1985; 40: 424-429Crossref PubMed Scopus (148) Google Scholar,5Heitmeier M.R. Arnush M. Scarim A.L. Corbett J.A. J. Biol. Chem. 2001; 276: 11151-11158Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). One important source of IL-1 within the islet is the resident macrophage, which produces IL-1 on activation by such stimuli as TNF-α and LPS (6Arnush M. Scarim A.L. Heitmeier M.R. Kelly C.B. Corbett J.A. J. Immunol. 1998; 160: 2684-2691PubMed Google Scholar). Studies have shown that activated intraislet macrophages release IL-1 in sufficient quantities within the microenvironment of the islet to stimulate β cell production of nitric oxide and nitric oxide-dependent β cell dysfunction, events that are potentiated by the presence of exogenous IFN-γ (6Arnush M. Scarim A.L. Heitmeier M.R. Kelly C.B. Corbett J.A. J. Immunol. 1998; 160: 2684-2691PubMed Google Scholar, 7Arnush M. Heitmeier M.R. Scarim A.L. Marino M.H. Manning P.T. Corbett J.A. J. Clin. Invest. 1998; 102: 516-526Crossref PubMed Scopus (216) Google Scholar).Viral infection has been implicated as one environmental factor that may trigger the initial autoimmune reaction that targets and destroys β cells in genetically susceptible individuals (8Yoon J.W. Diabetes Metab. Rev. 1995; 11: 83-107Crossref PubMed Scopus (69) Google Scholar, 9von Herrath M.G. Oldstone M.B. Curr. Opin. Immunol. 1996; 8: 878-885Crossref PubMed Scopus (109) Google Scholar, 10Bach J.F. Endocr. Rev. 1994; 15: 516-542Crossref PubMed Scopus (761) Google Scholar). Viruses have been isolated from the pancreata of acutely diabetic deceased patients, and viral-specific IgM antibodies have been isolated from newly diagnosed diabetic patients (8Yoon J.W. Diabetes Metab. Rev. 1995; 11: 83-107Crossref PubMed Scopus (69) Google Scholar, 10Bach J.F. Endocr. Rev. 1994; 15: 516-542Crossref PubMed Scopus (761) Google Scholar, 11Banatvala J.E. Bryant J. Schernthaner G. Borkenstein M. Schober E. De Brown D. Silva L.M. Menser M.A. Silink M. Lancet. 1985; 1: 1409-1412Abstract PubMed Scopus (173) Google Scholar). Autoimmune diabetes can also be induced in genetically susceptible strains of rats and mice by viral infection (8Yoon J.W. Diabetes Metab. Rev. 1995; 11: 83-107Crossref PubMed Scopus (69) Google Scholar, 10Bach J.F. Endocr. Rev. 1994; 15: 516-542Crossref PubMed Scopus (761) Google Scholar, 12von Herrath M.G. Evans C.F. Horwitz M.S. Oldstone M.B. Immunol. Rev. 1996; 152: 111-143Crossref PubMed Google Scholar). Kilham rat virus-induced diabetes in diabetes-resistant BioBreeding rats is dependent on the presence of macrophages and associated with the increased expression of the macrophage-derived cytokines IL-12, IL-1β, and TNF-α, as well as the T-cell cytokine IFN-γ (13Chung Y.H. Jun H.S. Kang Y. Hirasawa K. Lee B.R. Van Rooijen N. Yoon J.W. J. Immunol. 1997; 159: 466-471PubMed Google Scholar). In addition, encephalomyocarditis virus-induced diabetes in DBA/2 mice can be attenuated by macrophage depletion (14Hirasawa K. Tsutsui S. Takeda M. Mizutani M. Itagaki S. Doi K. J. Gen. Virol. 1996; 77: 737-741Crossref PubMed Scopus (34) Google Scholar), daily administration of neutralizing antisera specific for IL-1β and TNF-α, or selective inhibition of iNOS using aminoguanidine (AG) (15Hirasawa K. Jun H.S. Maeda K. Kawaguchi Y. Itagaki S. Mikami T. Baek H.S. Doi K. Yoon J.W. J. Virol. 1997; 71: 4024-4031Crossref PubMed Google Scholar). This evidence suggests that viral infection can stimulate diabetes in genetically susceptible rodents and that disease development is dependent on the production of macrophage- and T-cell-derived cytokines and nitric oxide.One common feature of a viral infection is the formation of dsRNA, which accumulates during viral replication (16Jacobs B.L. Langland J.O. Virology. 1996; 219: 339-349Crossref PubMed Scopus (519) Google Scholar). dsRNA is an active component of a viral infection that stimulates host antiviral responses, including the production of cytokines and nitric oxide (17Clemens M.J. Int. J. Biochem. Cell Biol. 1997; 29: 945-949Crossref PubMed Scopus (169) Google Scholar, 18Proud C.G. Trends Biochem. Sci. 1995; 20: 241-246Abstract Full Text PDF PubMed Scopus (200) Google Scholar, 19Robertson H.D. Mathews M.B. Biochimie. 1996; 78: 909-914Crossref PubMed Scopus (84) Google Scholar, 20Williams B.R. Biochem. Soc. Trans. 1997; 25: 509-513Crossref PubMed Scopus (137) Google Scholar). The synthetic dsRNA molecule poly(I-C) also activates the antiviral response (16Jacobs B.L. Langland J.O. Virology. 1996; 219: 339-349Crossref PubMed Scopus (519) Google Scholar) and has been shown to stimulate the development of diabetes in diabetes-resistant BioBreeding rats and to accelerate disease development in diabetes-prone BioBreeding rats (21Ewel C.H. Sobel D.O. Zeligs B.J. Bellanti J.A. Diabetes. 1992; 41: 1016-1021Crossref PubMed Google Scholar, 22Sobel D.O. Newsome J. Ewel C.H. Bellanti J.A. Abbassi V. Creswell K. Blair O. Diabetes. 1992; 41: 515-520Crossref PubMed Scopus (73) Google Scholar). We have shown that dsRNA, in combination with IFN-γ, induces islet dysfunction and destruction by a mechanism that is dependent on the expression of iNOS and production of nitric oxide by β cells (23Heitmeier M.R. Scarim A.L. Corbett J.A. J. Biol. Chem. 1999; 274: 12531-12536Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar,24Scarim A.L. Arnush M. Blair L.A. Concepcion J. Heitmeier M.R. Scheuner D. Kaufman R.J. Ryerse J. Buller R.M.L. Corbett J.A. Am. J. Pathol. 2001; 159: 273-285Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). In addition, dsRNA + IFN-γ has been shown to stimulate macrophage activation, as evidenced by increased iNOS expression, nitric oxide production, and IL-1 release (23Heitmeier M.R. Scarim A.L. Corbett J.A. J. Biol. Chem. 1999; 274: 12531-12536Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). β cells also produce IL-1 in response to dsRNA + IFN-γ, and β-cell production of IL-1 appears to participate in dsRNA + IFN-γ-induced iNOS expression and inhibition of islet function (5Heitmeier M.R. Arnush M. Scarim A.L. Corbett J.A. J. Biol. Chem. 2001; 276: 11151-11158Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). These findings show that dsRNA can modulate islet function by stimulating the production of inflammatory molecules, such as IL-1 and nitric oxide. However, the mechanisms by which dsRNA stimulates the production of these potentially destructive molecules in islets have not been fully examined.NF-κB and interferon regulatory factor-1 (IRF-1) are two transcription factors that participate in gene activation in response to viral infection or dsRNA (25Visvanathan K.V. Goodbourn S. EMBO J. 1989; 8: 1129-1138Crossref PubMed Scopus (213) Google Scholar, 26Xanthoudakis S. Cohen L. Hiscott J. J. Biol. Chem. 1989; 264: 1139-1145Abstract Full Text PDF PubMed Google Scholar, 27Reis L.F. Harada H. Wolchok J.D. Taniguchi T. Vilcek J. EMBO J. 1992; 11: 185-193Crossref PubMed Scopus (220) Google Scholar, 28Du W. Thanos D. Maniatis T. Cell. 1993; 74: 887-898Abstract Full Text PDF PubMed Scopus (395) Google Scholar). These transcription factors regulate cellular antiviral responses, including the expression of antiviral proteins (type I IFN, PKR, and major histocompatibility complex class I), control of cell cycle progression, and induction of apoptosis (29Tamura T. Ishihara M. Lamphier M.S. Tanaka N. Oishi I. Aizawa S. Matsuyama T. Mak T.W. Taki S. Taniguchi T. Nature. 1995; 376: 596-599Crossref PubMed Scopus (418) Google Scholar, 30Hovanessian A.G. Semin. Virol. 1994; 4: 237-245Crossref Scopus (49) Google Scholar, 31Weiss E.H. Golden L. Fahrner K. Mellor A.L. Devlin J.J. Bullman H. Tiddens H. Bud H. Flavell R.A. Nature. 1984; 310: 650-655Crossref PubMed Scopus (221) Google Scholar). Binding elements for both IRF-1 and NF-κB are found in the promoter regions of the rat, mouse, and human iNOS genes (32Beck K.F. Sterzel R.B. FEBS Lett. 1996; 394: 263-267Crossref PubMed Scopus (76) Google Scholar, 33Chu S.C. Wu H.P. Banks T.C. Eissa N.T. Moss J. J. Biol. Chem. 1995; 270: 10625-10630Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 34Xie Q.W. Whisnant R. Nathan C. J. Exp. Med. 1993; 177: 1779-1784Crossref PubMed Scopus (1020) Google Scholar). In addition, IRF-1 and NF-κB have been shown to physically interact at the iNOS promoter region, potentially leading to the synergistic activation of iNOS expression observed when both transcription factors are activated (35Saura M. Zaragoza C. Bao C. McMillan A. Lowenstein C.J. J. Mol. Biol. 1999; 289: 459-471Crossref PubMed Scopus (152) Google Scholar). dsRNA-stimulated activation of both NF-κB and IRF-1 have been shown to require activation of PKR in mouse embryonic fibroblasts (36Kumar A. Yang Y.L. Flati V. Der S. Kadereit S. Deb A. Haque J. Reis L. Weissmann C. Williams B.R. EMBO J. 1997; 16: 406-416Crossref PubMed Scopus (314) Google Scholar). NF-κB appears to be required for dsRNA + IFN-γ-induced iNOS expression and nitric oxide production by rat and human islets (37Blair L.A. Heitmeier M.R. Scarim A.L. Maggi Jr., L.B. Corbett J.A. Diabetes. 2001; 50: 283-290Crossref PubMed Scopus (22) Google Scholar), as well as for iNOS and IL-1 expression by mouse peritoneal macrophages (38Heitmeier M.R. Scarim A.L. Corbett J.A. J. Biol. Chem. 1998; 273: 15301-15307Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar).IRF-1 is a member of a large family of transcription factors activated in response to IFNs. All members of the IRF family of transcription factors bind to the IFN-stimulated response element located in the promoters of many IFN-inducible genes. Some IRFs, such as IRF-1 and ISGF3, activate mRNA transcription, whereas other IRFs, including IRF-2 and ICSBP, repression transcription (39Pitha P.M. Au W.C. Lowther W. Juang Y.T. Schafer S.L. Burysek L. Hiscott J. Moore P.A. Biochimie. 1998; 80: 651-658Crossref PubMed Scopus (73) Google Scholar). IRF-1 is an inducible transcription factor expressed in response to IFN-γ, viral infection, dsRNA, and the cytokines IL-1, IL-6, and TNF-α (40Kamijo R. Harada H. Matsuyama T. Bosland M. Gerecitano J. Shapiro D. Le J. Koh S.I. Kimura T. Green S.J. Mak T.W. Taniguchi T. Vilcek J. Science. 1994; 263: 1612-1615Crossref PubMed Scopus (782) Google Scholar). The IRF-1 gene promoter region contains binding elements for both NF-κB and STAT1 (γ-activated site). Binding of either transcription factor to the IRF-1 promoter region is sufficient to induce IRF-1 expression; however, the presence of both NF-κB and STAT1 binding greatly increases IRF-1 transcription (41Gupta S. Xia D. Jiang M. Lee S. Pernis A.B. J. Immunol. 1998; 161: 5997-6004PubMed Google Scholar, 42Pine R. Nucleic Acids Res. 1997; 25: 4346-4354Crossref PubMed Scopus (141) Google Scholar). IRF-1 is required for LPS + IFN-γ-induced iNOS expression by macrophages (40Kamijo R. Harada H. Matsuyama T. Bosland M. Gerecitano J. Shapiro D. Le J. Koh S.I. Kimura T. Green S.J. Mak T.W. Taniguchi T. Vilcek J. Science. 1994; 263: 1612-1615Crossref PubMed Scopus (782) Google Scholar) and appears to participate in IL-1-induced nitric oxide production by mouse islets (43Flodstrom M. Eizirik D.L. Endocrinology. 1997; 138: 2747-2753Crossref PubMed Scopus (66) Google Scholar, 44Pavlovic D. Chen M.C. Gysemans C.A. Mathieu C. Eizirik D.L. Eur. Cytokine Netw. 1999; 10: 403-411PubMed Google Scholar).In this study, we examined the role of the inducible transcription factor IRF-1 in dsRNA + IFN-γ-induced iNOS expression and nitric oxide production by both mouse islets and peritoneal macrophages. We show that although IRF-1 is required for dsRNA + IFN-γ-induced iNOS expression and nitric oxide production by mouse macrophages, dsRNA + IFN-γ-induced iNOS expression and nitric oxide production by mouse islets are IRF-1-independent. In addition, the antiviral protein PKR, which is thought to regulate IRF-1 expression in response to dsRNA, is not required for dsRNA + IFN-γ-stimulated IRF-1 expression by mouse islets or peritoneal macrophages. These results suggest that dsRNA + IFN-γ stimulates iNOS expression by two distinct PKR-independent mechanisms, one that is IRF-1-dependent in macrophages and another that is IRF-1-independent in islets.DISCUSSIONBoth genetic and environmental determinants are thought to participate in the development of autoimmune diabetes. Viral infection has been implicated as one environmental factor that may trigger the initial destruction of β cells during the development of diabetes (8Yoon J.W. Diabetes Metab. Rev. 1995; 11: 83-107Crossref PubMed Scopus (69) Google Scholar, 9von Herrath M.G. Oldstone M.B. Curr. Opin. Immunol. 1996; 8: 878-885Crossref PubMed Scopus (109) Google Scholar, 10Bach J.F. Endocr. Rev. 1994; 15: 516-542Crossref PubMed Scopus (761) Google Scholar). Analysis of animal models suggests that inflammatory cytokines such as IL-1, TNF-α, and IFN-γ, as well as nitric oxide, may participate in the development of viral-induced diabetes (13Chung Y.H. Jun H.S. Kang Y. Hirasawa K. Lee B.R. Van Rooijen N. Yoon J.W. J. Immunol. 1997; 159: 466-471PubMed Google Scholar). dsRNA is an active component of a viral infection that stimulates antiviral responses in infected cells (16Jacobs B.L. Langland J.O. Virology. 1996; 219: 339-349Crossref PubMed Scopus (519) Google Scholar). Treatment of rat and human islets and primary β cells with dsRNA + IFN-γ results in a potent inhibition of glucose-stimulated insulin secretion and islet degeneration, events that require β cell production of nitric oxide (23Heitmeier M.R. Scarim A.L. Corbett J.A. J. Biol. Chem. 1999; 274: 12531-12536Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). However, the signaling mechanisms required for dsRNA + IFN-γ-induced iNOS expression and nitric oxide-dependent islet dysfunction have yet to be defined.In this study, we examined the role of the inducible transcription factor IRF-1 in dsRNA + IFN-γ-induced iNOS expression and nitric oxide production by mouse islets. We show that dsRNA (in the form of poly(I-C)) stimulates IRF-1 expression by mouse islets to levels similar to those stimulated by IFN-γ. Importantly, the level of IRF-1 expressed in response to the combination of dsRNA and IFN-γ appears to be equivalent to the additive effects of either dsRNA or IFN-γ alone on IRF-1 expression. These findings suggest that dsRNA and IFN-γ stimulate IRF-1 expression by distinct pathways. Indeed, the promoter region of the IRF-1 gene contains binding elements for both NF-κB (κB site) and STAT1 (γ-activated site; Refs. 41Gupta S. Xia D. Jiang M. Lee S. Pernis A.B. J. Immunol. 1998; 161: 5997-6004PubMed Google Scholar, 42Pine R. Nucleic Acids Res. 1997; 25: 4346-4354Crossref PubMed Scopus (141) Google Scholar). These binding elements overlap, creating a composite γ-activated site-κB promoter element to which NF-κB and STAT1 bind in a mutually exclusive and independent manner (42Pine R. Nucleic Acids Res. 1997; 25: 4346-4354Crossref PubMed Scopus (141) Google Scholar). dsRNA has been shown to activate NF-κB in several cell types, including islets (37Blair L.A. Heitmeier M.R. Scarim A.L. Maggi Jr., L.B. Corbett J.A. Diabetes. 2001; 50: 283-290Crossref PubMed Scopus (22) Google Scholar, 38Heitmeier M.R. Scarim A.L. Corbett J.A. J. Biol. Chem. 1998; 273: 15301-15307Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 46Yang Y.L. Reis L.F. Pavlovic J. Aguzzi A. Schafer R. Kumar A. Williams B.R. Aguet M. Weissmann C. EMBO J. 1995; 14: 6095-6106Crossref PubMed Scopus (562) Google Scholar), whereas STAT1 is activated in response to IFN-γ (55Stark G.R. Kerr I.M. Williams B.R. Silverman R.H. Schreiber R.D. Annu. Rev. Biochem. 1998; 67: 227-264Crossref PubMed Scopus (3361) Google Scholar). Simultaneous activation of NF-κB and STAT1 (by TNF-α and IFN-γ, respectively) has been shown to stimulate the synergistic induction of IRF-1 that is mediated by the composite γ-activated site-κB element in HepG2 cells (42Pine R. Nucleic Acids Res. 1997; 25: 4346-4354Crossref PubMed Scopus (141) Google Scholar). Our observations with dsRNA and IFN-γ are consistent with these findings, suggesting cooperation between NF-κB and STAT1 that leads to increased IRF-1 expression by islets.Islets contain 10–15 resident macrophages that may contribute to β cell destruction by producing the inflammatory cytokine IL-1 and nitric oxide (56Lacy P.E. Finke E.H. Am. J. Pathol. 1991; 138: 1183-1190PubMed Google Scholar). Arnush et al. (6Arnush M. Scarim A.L. Heitmeier M.R. Kelly C.B. Corbett J.A. J. Immunol. 1998; 160: 2684-2691PubMed Google Scholar, 7Arnush M. Heitmeier M.R. Scarim A.L. Marino M.H. Manning P.T. Corbett J.A. J. Clin. Invest. 1998; 102: 516-526Crossref PubMed Scopus (216) Google Scholar) showed that activation of resident macrophages within the microenvironment of the islet leads to iNOS expression and nitric oxide production by β cells by a mechanism that is dependent on macrophage IL-1 release. In addition, dsRNA + IFN-γ stimulates macrophage activation, as evidenced by increased iNOS expression, nitric oxide production, and IL-1 release (38Heitmeier M.R. Scarim A.L. Corbett J.A. J. Biol. Chem. 1998; 273: 15301-15307Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 54Maggi Jr., L.B. Heitmeier M.R. Scheuner D. Kaufman R.J. Buller R.M. Corbett J.A. EMBO J. 2000; 19: 3630-3638Crossref PubMed Scopus (68) Google Scholar). In this study, we also examined the role of IRF-1 in the activation of mouse peritoneal macrophages. We show that dsRNA fails to stimulate IRF-1 expression by macrophages. This is in contrast to mouse islets, where IRF-1 expression is greatly increased after a 3-h treatment. However, dsRNA appears to potentiate IFN-γ-stimulated IRF-1 expression by macrophages. This is similar to findings in mouse islets, where maximal IRF-1 expression requires the activation of two transcription factors (NF-κB and STAT1).IRF-1 is required for LPS + IFN-γ-induced iNOS expression by macrophages, because LPS + IFN-γ fails to induce iNOS expression in macrophages isolated from IRF-1-deficient mice (40Kamijo R. Harada H. Matsuyama T. Bosland M. Gerecitano J. Shapiro D. Le J. Koh S.I. Kimura T. Green S.J. Mak T.W. Taniguchi T. Vilcek J. Science. 1994; 263: 1612-1615Crossref PubMed Scopus (782) Google Scholar). We show that dsRNA + IFN-γ also fails to induce iNOS expression and nitric oxide production by peritoneal macrophages isolated from IRF-1−/− mice. This finding is in contrast to mouse islets, where dsRNA + IFN-γ induces iNOS expression and nitric oxide production in the absence of IRF-1. These results suggest that dsRNA + IFN-γ stimulates iNOS expression by two distinct mechanisms, one that is IRF-1-dependent (macrophages) and another that is IRF-1-independent (islets).Although IRF-1 is required for dsRNA + IFN-γ-induced nitric oxide production by macrophages, we do not see a decrease in dsRNA + IFN-γ-induced nitric oxide production by islets isolated from IRF-1−/− mice, which contain resident macrophages. These results imply that resident islet macrophages do not contribute significantly to total islet nitric oxide production in response to dsRNA + IFN-γ. This finding is in concordance with previous studies showing that dsRNA + IFN-γ induces iNOS expression and nitric oxide production by rat islets depleted of resident macrophages (23Heitmeier M.R. Scarim A.L. Corbett J.A. J. Biol. Chem. 1999; 274: 12531-12536Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar).One mechanism by which macrophages may contribute to dsRNA + IFN-γ-induced islet dysfunction is by the production and release of IL-1, which may then stimulate β cells to express iNOS and produce nitric oxide. We show that dsRNA + IFN-γ induces IL-1 release to similar levels in peritoneal macrophages isolated from IRF-1−/− and IRF-1+/+ mice. β cells also produce and release IL-1 in response to dsRNA + IFN-γ. Recent studies have shown that β cell production of IL-1β partially mediates dsRNA + IFN-γ-induced iNOS expression and nitric oxide production by rat islets and primary β cells (5Heitmeier M.R. Arnush M. Scarim A.L. Corbett J.A. J. Biol. Chem. 2001; 276: 11151-11158Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). In addition, dsRNA + IFN-γ-induced nitric oxide production is reduced by ∼50% in islets isolated from mice deficient in the type I IL-1 receptor. 2L. A. Blair and J. A. Corbett, unpublished observations. We show that dsRNA + IFN-γ induces IL-1 expression by peritoneal macrophages and islets and IL-1 release by peritoneal macrophages isolated from both IRF-1−/− and IRF-1+/+ mice. Importantly, cycloheximide prevents dsRNA + IFN-γ-induced IL-1β mRNA accumulation by islets isolated from IRF-1−/− mice. This implies that an inducible factor other than IRF-1 is required for dsRNA + IFN-γ-induced IL-1 expression by islets. Potential factors whose expression may be induced in islets by dsRNA are currently being examined by our laboratory.We have shown that dsRNA + IFN-γ-induced iNOS expression and nitric oxide production by mouse islets and peritoneal macrophages do not require the antiviral kinase PKR (37Blair L.A. Heitmeier M.R. Scarim A.L. Maggi Jr., L.B. Corbett J.A. Diabetes. 2001; 50: 283-290Crossref PubMed Scopus (22) Google Scholar, 54Maggi Jr., L.B. Heitmeier M.R. Scheuner D. Kaufman R.J. Buller R.M. Corbett J.A. EMBO J. 2000; 19: 3630-3638Crossref PubMed Scopus (68) Google Scholar). In addition, we have shown that dsRNA-stimulated NF-κB activation in both islets and peritoneal macrophages is PKR-independent (37Blair L.A. Heitmeier M.R. Scarim A.L. Maggi Jr., L.B. Corbett J.A. Diabetes. 2001; 50: 283-290Crossref PubMed Scopus (22) Google Scholar, 54Maggi Jr., L.B. Heitmeier M.R. Scheuner D. Kaufman R.J. Buller R.M. Corbett J.A. EMBO J. 2000; 19: 3630-3638Crossref PubMed Scopus (68) Google Scholar). Consistent with these findings, we show that dsRNA and dsRNA + IFN-γ-stimulated IRF-1 expression is also independent of PKR. These results are in contrast to previous studies showing that PKR is required for dsRNA-induced IRF-1 and NF-κB activation by mouse embryonic fibroblasts (36Kumar A. Yang Y.L. Flati V. Der S. Kadereit S. Deb A. Haque J. Reis L. Weissmann C. Williams B.R. EMBO J. 1997; 16: 406-416Crossref PubMed Scopus (314) Google Scholar, 46Yang Y.L. Reis L.F. Pavlovic J. Aguzzi A. Schafer R. Kumar A. Williams B.R. Aguet M. Weissmann C. EMBO J. 1995; 14: 6095-6106Crossref PubMed Scopus (562) Google Scholar). The mechanisms responsible for the differences in dsRNA responsiveness of embryonic fibroblasts compared with islets or macrophages are unknown. However, recent studies by Iordanov et al. (57Iordanov M.S. Wong J. Bell J.C. Magun B.E. Mol. Cell. Biol. 2001; 21: 61-72Crossref PubMed Scopus (92) Google Scholar) question the role of PKR in dsRNA-stimulated NF-κB activation in mouse embryonic fibroblasts.In summary, we have examined the potential role of the inducible transcription factor IRF-1 in dsRNA + IFN-γ-induced iNOS expression and nitric oxide production by both mouse islets and peritoneal macrophages. We show that dsRNA (or dsRNA + IFN-γ) stimulates IRF-1 expression by mouse islets and peritoneal macrophages and that this expression is PKR-independent. Importantly, we show that IRF-1 is not required for dsRNA + IFN-γ-induced iNOS expression and nitric oxide production by mouse islets. In contrast, dsRNA + IFN-γ-induced iNOS expression and nitric oxide production by mouse peritoneal macrophages requires IRF-1 expression. We also show that IRF-1 is not required for dsRNA-induced IL-1 expression by mouse peritoneal macrophages or islets. These results suggest that IRF-1 plays a minimal role in mediating the destructive effects of dsRNA and IFN-γ on mouse islets. Autoimmune diabetes is characterized by a local inflammatory reaction in and around the pancreatic islets of Langerhans, followed by selective destruction of insulin-producing β cells (1Gepts W. Diabetes. 1965; 14: 619-633Crossref PubMed Scopus (969) Google Scholar, 2Sibley R.K. Sutherland D.E. Goetz F. Michael A.F. Lab. Invest. 1985; 53: 132-144PubMed Google Scholar). This inflammatory reaction consists of macrophages, monocytes, T and B lymphocytes, and natural killer cells that infiltrate into the islet after an initial triggering event to cause β cell destruction (2Sibley R.K. Sutherland D.E. Goetz F. Michael A.F. Lab. Invest. 1985; 53: 132-144PubMed Google Scholar, 3Lee K.U. Amano K. Yoon J.W. Diabetes. 1988; 37: 989-991Crossref PubMed Scopus (221) Google Scholar). Although the mechanism associated with the autoimmune reaction leading to the development of diabetes has been studied in detail, few studies have examined the precipitating events that trigger the initial destruction of β cells leading to this autoimmune inflammatory reaction. We and others have shown that IL-11 induces an inhibition of insulin secretion and the subsequent de" @default.
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• W2014906922 title "Role of Interferon Regulatory Factor-1 in Double-stranded RNA-induced iNOS Expression by Mouse Islets" @default.
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