Interleukin (IL)-1β toxicity to islet β cells: Efaroxan exerts a complete protection

✍ Scribed by Gianpaolo Papaccio; Antonio Graziano; Salvatore Valiante; Riccardo D'Aquino; Salvatore Travali; Ferdinando Nicoletti

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: English
• Weight: 371 KB
• Volume: 203
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.20198

✦ Synopsis

Abstract

Interleukin (IL)‐1β‐treated rat islets of Langerhans were exposed in vitro either to the imidazoline compound, Efaroxan, or to the selective inducible nitric oxide synthase (iNOS) inhibitor, 1400W, in a medium containing a high concentration of glucose (16.7 mmol/L). Our data have evidenced the following: (i) addition of Efaroxan to islet cultures inhibited IL‐1β activation of ICE (cysteine protease IL‐1β converting enzyme) while addition of 1400W did not; (ii) Efaroxan completely inhibited IL‐1β‐induced suppression of insulin secretion and induction of iNOS mRNA transcripts, and, in addition, counteracted islet β‐cell protein profile alterations, Bax‐cytochrome c translocation, caspase activation, and apoptosis; (iii) 1400W inhibited IL‐1β induction of iNOS, but failed to completely counteract the other cytotoxic effects; (iv) the two compounds, moreover, exerted different effects on manganese superoxide dismutase (MnSOD), in fact, while Efaroxan inhibited the early stimulatory effect of IL‐1β on MnSOD, 1400W did not. Thus, Efaroxan completely protected islet β cells from damage caused by IL‐1β‐induced toxicity, while compound 1400W only inhibited NO radical production without altering the cytokine's cytotoxicity. Our observations have evidenced that suppression of ICE activation is required to counteract IL‐1β‐mediated islet β cell toxicity, and that IL‐1β‐induced apoptosis is NO‐independent and involves the cytochrome c‐mitochondrial pathway. © 2004 Wiley‐Liss, Inc.