IFN-γ/TNF-α synergism as the final effector in autoimmune diabetes: a key role for STAT1/IFN regulatory factor-1 pathway in pancreatic β cell death

K Suk, S Kim, YH Kim, KA Kim, I Chang… - The Journal of …, 2001 - journals.aai.org
K Suk, S Kim, YH Kim, KA Kim, I Chang, H Yagita, M Shong, MS Lee
The Journal of Immunology, 2001journals.aai.org
Abstract Fas ligand (FasL), perforin, TNF-α, IL-1, and NO have been considered as effector
molecule (s) leading to β cell death in autoimmune diabetes. However, the real culprit (s) in
β cell destruction have long been elusive, despite intense investigation. We and others have
demonstrated that FasL is not a major effector molecule in autoimmune diabetes, and
previous inability to transfer diabetes to Fas-deficient nonobese diabetic (NOD)-lpr mice was
due to constitutive FasL expression on lymphocytes from these mice. Here, we identified IFN …
Abstract
Fas ligand (FasL), perforin, TNF-α, IL-1, and NO have been considered as effector molecule (s) leading to β cell death in autoimmune diabetes. However, the real culprit (s) in β cell destruction have long been elusive, despite intense investigation. We and others have demonstrated that FasL is not a major effector molecule in autoimmune diabetes, and previous inability to transfer diabetes to Fas-deficient nonobese diabetic (NOD)-lpr mice was due to constitutive FasL expression on lymphocytes from these mice. Here, we identified IFN-γ/TNF-α synergism as the final effector molecules in autoimmune diabetes of NOD mice. A combination of IFN-γ and TNF-α, but neither cytokine alone, induced classical caspase-dependent apoptosis in insulinoma and pancreatic islet cells. IFN-γ treatment conferred susceptibility to TNF-α-induced apoptosis on otherwise resistant insulinoma cells by STAT1 activation followed by IFN regulatory factor (IRF)-1 induction. IRF-1 played a central role in IFN-γ/TNF-α-induced cytotoxicity because inhibition of IRF-1 induction by antisense oligonucleotides blocked IFN-γ/TNF-α-induced cytotoxicity, and transfection of IRF-1 rendered insulinoma cells susceptible to TNF-α-induced cytotoxicity. STAT1 and IRF-1 were expressed in pancreatic islets of diabetic NOD mice and colocalized with apoptotic cells. Moreover, anti-TNF-α Ab inhibited the development of diabetes after adoptive transfer. Taken together, our results indicate that IFN-γ/TNF-α synergism is responsible for autoimmune diabetes in vivo as well as β cell apoptosis in vitro and suggest a novel signal transduction in IFN-γ/TNF-α synergism that may have relevance in other autoimmune diseases and synergistic anti-tumor effects of the two cytokines.
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