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Original Article

A20 Inhibits Cytokine-Induced Apoptosis and Nuclear Factor B–Dependent Gene Activation in Islets

^a Immunobiology Research Center, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215
^b Joslin Center for Diabetes, Boston, Massachusetts 02215
Immunobiology Research Center, Harvard Medical School, Beth Israel Deaconess Medical Center, 99 Brookline Ave., Boston, MA 02215.617-632-0880617-632-0840

cferran{at}caregroup.harvard.edu

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease resulting from apoptotic destruction of β cells in the islets of Langerhans. Low expression of antioxidants and a predilection to produce nitric oxide (NO) have been shown to underscore β cell apoptosis. With this perspective in mind, we questioned whether β cells could mount an induced protective response to inflammation. Here we show that human and rat islets can be induced to rapidly express the antiapoptotic gene A20 after interleukin (IL)-1β activation. Overexpression of A20 by means of adenovirus-mediated gene transfer protects islets from IL-1β and interferon –induced apoptosis. The cytoprotective effect of A20 against apoptosis correlates with and is dependent on the abrogation of cytokine-induced NO production. The inhibitory effect of A20 on cytokine-stimulated NO production is due to transcriptional blockade of inducible NO synthase (iNOS) induction; A20 inhibits the activation of the transcription factor nuclear factor B at a level upstream of IB degradation. These data demonstrate a dual antiapoptotic and antiinflammatory function for A20 in β cells. This qualifies A20 as part of the physiological cytoprotective response of islets. We propose that A20 may have therapeutic potential as a gene therapy candidate to achieve successful islet transplantation and the cure of IDDM.

Key Words: A20 • β cells • nuclear factor B • nitric oxide • apoptosis

1used in this paper: β-gal, β-galactosidase; EMSA, electrophoretic mobility shift assay; GSNO, S-nitrosoglutathione; IDDM, insulin-dependent diabetes mellitus; IB, inhibitor of NF-B; iNOS, inducible NO synthase; L-NIO, l-N5-(1-iminoethyl) ornithine, dihydrochloride; MnSOD, manganese superoxide dismutase; MOI, multiplicity of infection; NF-B, nuclear factor B; NO, nitric oxide; NOD, nonobese diabetic; NONOate, N-(2-aminoethyl)-N-(2-hydroxy-2-nitrosohydrazino-1,2-ethylenediamine; rAd, recombinant adenovirus; RT, reverse transcription; TRAF, TNF receptor–associated factor

Shane T. Grey, Immunobiology Research Center, Harvard Medical School, Beth Israel Deaconess Medical Center, 99 Brookline Ave., Boston, MA 02215. Phone: 617-632-0859; Fax: 617-632-0880; E-mail: sgrey@caregroup.harvard.edu

© 1999 The Rockefeller University Press

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