Role of p38 mitogen-activated protein kinase (p38 MAPK) in cytokine-induced rat islet cell apoptosis

The signaling pathways mediating nitric oxide production and apoptosis in p ancreatic beta -cells are not fully understood. We investigated cytokine-in duced protein phosphorylation events in insulin-producing cells and evaluat ed their role in inducible nitric oxide synthase (iNOS) induction and cell death. Interleukin-1 beta (IL-1 beta), but not interferon-gamma (IFN-gamma) , induced phosphorylation of p38 mitogen-activated protein kinase, c-Jun NH 2-terminal kinase, and mitogen- and stress-activated protein kinase 1 (MSK1 ) in rat insulin-producing RINm5F cells. This was paralleled by an increase d phosphorylation of the transcription factors activating transcription fac tor-2 (ATF-2) and cAMP-responsive element-binding protein (CREB). The p38 i nhibitor SB203580 prevented cytokine-induced phosphorylation of CREB and MS K1, but not of ATF-2. IFN-gamma induced the phosphorylation of signal trans ducer and activator of transcription 1, The combination of IL-1 beta and IF N-gamma increased both apoptosis and necrosis in rat islet cells. SB203580, but not the extracellular signal-regulated kinase inhibitor PD98059, parti ally prevented cytokine-induced apoptosis, an effect that was not associate d with reduced nitrite production or lowered iNOS expression. In conclusion , cytokine-induced p38 activation participates in beta -cell apoptosis, pos sibly by a nitric oxide-independent mechanism or by enhancing the sensitivi ty to nitric oxide. (C) 2001 Elsevier Science Inc. AU rights reserved.