Apoptosis of Human Islet Cells by Cytokines
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
FasL, perforin, TNFα, IL-1 and NO have been considered as effector molecule(s) leading to β-cell death in autoimmune diabetes. However, the real culprit(s) of β-cell destruction have long been elusive despite intense investigation. Previously we have suggested IFNγ/TNFα synergism as the final effector molecules in autoimmune diabetes of NOD mice. A combination of IFNγ and TNFα but neither cytokine alone, induced classical caspase-dependent apoptosis in murine insulinoma and pancreatic islet cells. IFNγ treatment conferred susceptibility to TNFα-induced apoptosis on otherwise resistant murine insulinoma cells by STAT1 activation followed by IRF-1 induction. Here we report that IFNγ/TNFα synergism induces apoptosis of human pancreatic islet cells. We also observed STAT1 activation followed by IRF-1 induction by IFNγ treatment in human islet cells. Taken together, we suggest that IFNγ/TNFα synergism could be involved in human islet cell death in type 1 diabetes,similar to murine type 1 diabetes.
Abstract
FasL, perforin, TNFα, IL-1 and NO have been considered as effector molecule(s) leading to β-cell death in autoimmune diabetes. However, the real culprit(s) of β-cell destruction have long been elusive despite intense investigation. Previously we have suggested IFNγ/TNFα synergism as the final effector molecules in autoimmune diabetes of NOD mice. A combination of IFNγ and TNFα but neither cytokine alone, induced classical caspase-dependent apoptosis in murine insulinoma and pancreatic islet cells. IFNγ treatment conferred susceptibility to TNFα-induced apoptosis on otherwise resistant murine insulinoma cells by STAT1 activation followed by IRF-1 induction. Here we report that IFNγ/TNFα synergism induces apoptosis of human pancreatic islet cells. We also observed STAT1 activation followed by IRF-1 induction by IFNγ treatment in human islet cells. Taken together, we suggest that IFNγ/TNFα synergism could be involved in human islet cell death in type 1 diabetes,similar to murine type 1 diabetes.
참고문헌 (18)
- Kim, S., "Essential role for signal transducer and activator of transcription-1 in pancreatic beta-cell death and autoimmune type 1 diabetes of nonobese diabetic mice", DIABETES, 56(10), pp.2561~2568, AMER DIABETES ASSOC
- Suk, K., "IFN-gamma", TNF-alpha synergism as the final effector in autoimmune diabetes: a key role for STAT1, J. Immunol, pp.2001, 166[DOI]
- Kim, H. S., "TLR2 as a link between β-cell injury and initiation of autoimmune diabetes", Immunity, 27, pp.321~333 (2007)
- Turley, S., "Physiological beta cell death triggers priming of self-reactiveT cells by dendritic cells in a type-1 diabetes model", J. Exp. Med, 198, pp.1527~1537 (2003)
- Wicker, L. S., "Transfer of autoimmune diabetes mellitus with splenocytes from nonobese diabetic (NOD) mice", Diabetes, 35, pp.855~860 (1986)
- Wang, Y., "The role of CD4＋ and CD8＋ T cells in the destruction of islet grafts by spontaneously diabetic mice", Proc. Natl. Acad. Sci. U. S. A, 88, pp.527~531 (1991)
- Katz, J. D., "T helper cell subsets in insulin-dependent diabetes", Science, 268, pp.1185~1188 (1995)
- Kurrer, M. O., "Beta cell apoptosis in T cell-mediated autoimmunediabetes", Proc. Natl. Acad. Sci. U. S. A, 94, pp.213~218 (1997)
- Kim, Y. H., "Apoptosis of pancreatic beta- cells detected in accelerated diabetes of NOD mice: no role of Fas-Fas ligand interaction in autoimmune diabetes", Eur. J. Immunol, 29, pp.455~465 (1999)
- Amrani, A., "Perforin-independent beta-cell destruction by diabetogenic CD8(＋) T lymphocytes in transgenic nonobese diabetic mice", J. Clin. Invest, 103, pp.1201~1209 (1999)
- Kim, S., "Inhibition of autoimmune diabetes by Fas ligand: the paradox is solved", J. Immunol, 164, pp.2931~2936 (2000)
- Ricordi, C., "Automated method for isolation of human pancreatic islets", Diabetes, 37, pp.413~420 (1988)
- Rabinovitch, A., "Cytotoxic effects of cytokines on human pancreatic islet cells in monolayer culture", J. Clin. Endocrinol. Metab, 71, pp.152~156 (1990)
- Rabinovitch, A., "Human pancreatic islet beta-cell destruction by cytokines is independent of nitric oxide production", J. Clin. Endocrinol.Metab, 79, pp.1058~1062 (1994)
- Delaney, C. A, "Cytokines induce deoxyribonucleic acid strand breaks and apoptosis in human pancreatic islet cells", Endocrinology, 138, pp.2610~2614 (1997)
- Marselli, L., "Th2 cytokines have a partial, direct protective effect on the function and survival of isolated human islets exposed to combined proinflammatory and Th1 cytokines", J. Clin. Endocrinol. Metab, 86, pp.4974~4978 (2001)
- Suk, K., "Interferon gamma (IFNgamma) and tumor necrosis factor alpha synergism in ME-180 cervical cancer cell apoptosis and necrosis. IFNgamma inhibits cytoprotective NF-kappa B through STAT1", IRF-1 pathways, 2001, pp.276, 13153~13159
- Gabriel Nunez, "Cytokines Tumor Necrosis Factor-alpha and Interferon-gamma Induce Pancreatic beta-Cell Apoptosis through STAT1-mediated Bim Protein Activation", JOURNAL OF BIOLOGICAL CHEMISTRY, 286(45), pp.39632~39643, AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC