A20 inhibits cytokine-induced apoptosis and nuclear factor κB–dependent gene activation in islets

ST Grey, MB Arvelo, W Hasenkamp, FH Bach… - The Journal of …, 1999 - rupress.org
ST Grey, MB Arvelo, W Hasenkamp, FH Bach, C Ferran
The Journal of experimental medicine, 1999rupress.org
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 …
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 γ–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 κB at a level upstream of IκBα 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.
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