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.
Saldeen
Johan
J
Department of Medical Cell Biology, Uppsala University, Biomedicum, PO Box 571, S-751 23 Uppsala, Sweden. Johan.Saldeen@medcellbiol.uu.se
Welsh
Nils
N
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D016328:NF-kappa B; D011725:Pyridines; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D048056:Mitogen-Activated Protein Kinase 9; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580