p38 MAPK inhibits JNK2 and mediates cytokine-activated iNOS induction and apoptosis independently of NF-KB translocation in insulin-producing cells.

The signaling pathways mediating nitric oxide production and apoptosis in pancreatic beta-cells are incompletely characterized. We report here that the inhibitor of p38 MAPK (p38), SB203580 (10-100 microM) inhibits interleukin-1beta (IL-1beta)-induced nitric oxide production in rat insulin-producing RINm5F cells. SB203580 also counteracts apoptosis induced by a combination of IL-1beta and interferon-gamma. However, the contribution by p38 to the induction of inducible nitric oxide synthase (iNOS) and apoptosis is independent of NF-kappaB nuclear translocation since SB203580 does not prevent IL-1beta-induced DNA-binding of this transcription factor. Furthermore, SB203580 alone leads to phosphorylation of JNK2 which may reflect inhibition of a p38-activated phosphatase. It is concluded that p38 mediates cytokine-induced iNOS-induction and apoptosis independently of NF-kappaB translocation. Moreover, a preventive effect on iNOS induction and apoptosis by inhibition of p38 may be partly masked due to simultaneous activation of JNK2 in pancreatic RINm5F cells.