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Nuclear Factor-B Regulates ß-Cell Death

A Critical Role for A20 in ß-Cell Protection

¹ Arthritis and Inflammation Program, Garvan Institute for Medical Research, Darlinghurst, New South Wales, Australia
² Biology and Chemistry Section, CombiMatrix Corporation, Mukilteo, Washington

Address correspondence and reprint requests to Dr. Shane T Grey,Gene Therapy & Autoimmunity Group, Arthritis and Inflammation Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010 Australia. E-mail: s.grey{at}garvan.org.au

Abbreviations: FACS, fluorescence-activated cell sorter; FADD, Fas-associated death domain; FADD-DN, FADD dominant negative inhibitor; ß-gal, ß-galactosidase; IL, interleukin; IFN, interferon; IB, inhibitor of NF-B; NF-B, nuclear factor-B; NIK, NF-B-inducing kinase; PKD, protein kinase D; Th, T-helper; TLR, Toll-like receptor; TNF, tumor necrosis factor; TNF-R, TNF receptor; TRAF, TNF receptor–associated factor

Apoptotic ß-cell death is central to the pathogenesis of type 1 diabetes and may be important in islet graft rejection. Despite this, genetic control of ß-cell apoptosis is only poorly understood. We report that inhibition of gene transcription sensitized ß-cells to tumor necrosis factor (TNF)-–induced apoptosis, indicating the presence of a regulated antiapoptotic response. Using oligonucleotide microarrays and real-time PCR, we identified TNFAIP3/A20 as the most highly regulated antiapoptotic gene expressed in cytokine-stimulated human and mouse islets. Cytokine induction of A20 mRNA in primary islets and insulinoma cells was rapid and observed within 1 h, consistent with A20 being an immediate early response gene in ß-cells. Regulation of A20 was nuclear factor-B (NF-B)–dependent, two NF-B sites within the A20 promoter were found to be necessary and sufficient for A20 expression in ß-cells. Activation of NF-B by TNF receptor–associated factor (TRAF) 2, TRAF6, NF-B–inducing kinase, or protein kinase D, which transduce signals downstream of Toll-like receptors, TNF receptors, and free radicals, respectively, were all potent activators of the A20 promoter. Moreover, A20 expression was induced in transplanted islets in vivo. Finally, A20 expression was sufficient to protect ß-cells from TNF-induced apoptosis. These data demonstrate that A20 is the cardinal antiapoptotic gene in ß-cells. Further, A20 expression is NF-B dependent, thus linking islet proinflammatory gene responses with protection from apoptosis.

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