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Proc. Natl. Acad. Sci. USA, Published online before print January 31, 2007 NF-κB prevents β cell death and autoimmune diabetes in NOD mice

Abstract

Sunshin Kim *, Isabelle Millet , Hun Sik Kim *, Ja Young Kim *, Myoung Sook Han *, Moon-Kyu Lee *, Kwang-Won Kim *, Robert S. Sherwin , Michael Karin , and Myung-Shik Lee *

^*Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Kangnam-ku, Seoul 135-710, Korea; Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, TMP532, P.O. Box 208020, New Haven, CT 06520-8020; and Department of Pharmacology, School of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723

Contributed by Michael Karin, December 6, 2006 (sent for reviewNovember 1, 2006)

Whereas NF-B has potent antiapoptotic function in most cell types, it was reported that in pancreatic β cells it serves a proapoptotic function and may contribute to the pathogenesis of autoimmune type 1 diabetes. To investigate the role of β cell NF-B in autoimmune diabetes, we produced transgenic mice expressing a nondegradable form of IB in pancreatic β cells (RIP-mIB mice). β cells of these mice were more susceptible to killing by TNF- plus IFN- but more resistant to IL-1β plus IFN- than normal β cells. Similar results were obtained with β cells lacking I ${kappa}$ B kinase β, a protein kinase required for NF-B activation.Inhibition of β cell NF-B accelerated the development of autoimmunediabetes in nonobese diabetic mice but had no effect on glucosetolerance or serum insulin in C57BL/6 mice, precluding a nonphysiological effect of transgene expression. Development of diabetes after transfer of diabetogenic CD4⁺ T cells was accelerated in RIP-mIB/nonobese diabetic mice and was abrogated by anti-TNF therapy. These results suggest that under conditions that resemble autoimmune type 1 diabetes, the dominant effect of NF-B is prevention of TNF-inducedapoptosis. This differs from the proapoptotic function of NF-B in IL-1β-stimulated β cells.

Author contributions: S.K., R.S.S., M.K., and M.-S.L. designed research; S.K., I.M., H.S.K., J.Y.K., M.S.H., and M.-S.L. performed research; I.M., M.-K.L., K.-W.K., R.S.S., M.K., and M.-S.L. contributed new reagents/analytic tools; S.K., H.S.K., M.-K.L., K.-W.K., R.S.S., M.K., and M.-S.L. analyzed data; and M.K. and M.-S.L. wrote the paper.

The authors declare no conflict of interest.

To whom correspondence may be addressed.

논문정보

형식Research article
게재일2007년 01월 (BRIC 등록일 )
연구진국내(교신)+국외 연구진
분야 의약학 > 면역의학

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