A20 Inhibits Cytokine-induced Apoptosis and Nuclear Factor B–dependent Gene Activation in Islets

Correspondence to: Christiane Ferran, Immunobiology Research Center, Harvard Medical School, Beth Israel Deaconess Medical Center, 99 Brookline Ave., Boston, MA 02215. Tel:617-632-0840 Fax:617-632-0880 E-mail:cferran{at}caregroup.harvard.edu.

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease resulting from apoptotic destruction of ß cells in the islets of Langerhans. Low expression of antioxidants and a predilection to produce nitric oxide (NO) have been shown to underscore ß cell apoptosis. With this perspective in mind, we questioned whether ß 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)-1ß activation. Overexpression of A20 by means of adenovirus-mediated gene transfer protects islets from IL-1ß 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 ß 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, ß cells, nuclear factor B, nitric oxide, apoptosis

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