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/TNF-
Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic 
Cell Death1
*
Clinical Research Center, Samsung Biomedical Research Institute, and
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea;
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan;
Department of Medicine, Chungnam University, Taejun, Korea; and
¶ Graduate School of East-West Medical Science, Kyunghee University, Seoul, Korea
Fas ligand (FasL), perforin, TNF-
, IL-1, and NO have been
considered as effector molecule(s) leading to 
cell death in
autoimmune diabetes. However, the real culprit(s) in 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-
/TNF- synergism as the final effector molecules
in autoimmune diabetes of NOD mice. A combination of IFN- and
TNF-, but neither cytokine alone, induced classical
caspase-dependent apoptosis in insulinoma and pancreatic islet cells.
IFN- treatment conferred susceptibility to TNF--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-/TNF--induced cytotoxicity because inhibition of IRF-1
induction by antisense oligonucleotides blocked IFN-/TNF--induced
cytotoxicity, and transfection of IRF-1 rendered insulinoma cells
susceptible to TNF--induced cytotoxicity. STAT1 and IRF-1 were
expressed in pancreatic islets of diabetic NOD mice and colocalized
with apoptotic cells. Moreover, anti-TNF- Ab inhibited the
development of diabetes after adoptive transfer. Taken together, our
results indicate that IFN-/TNF- synergism is responsible for
autoimmune diabetes in vivo as well as cell apoptosis in vitro and
suggest a novel signal transduction in IFN-/TNF- synergism that
may have relevance in other autoimmune diseases and synergistic
anti-tumor effects of the two cytokines.
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