Saldeen Johan, Welsh Nils
Department of Medical Cell Biology, Uppsala University, Biomedicum, PO Box 571, S-751 23 Uppsala, Sweden.
Eur Cytokine Netw. 2004 Jan-Mar;15(1):47-52.
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.
介导胰腺β细胞中一氧化氮生成和细胞凋亡的信号通路尚未完全明确。我们在此报告，p38丝裂原活化蛋白激酶（p38）的抑制剂SB203580（10 - 100微摩尔）可抑制白细胞介素-1β（IL-1β）诱导的大鼠胰岛素分泌细胞RINm5F中一氧化氮的生成。SB203580还可对抗由IL-1β和干扰素-γ联合诱导的细胞凋亡。然而，p38对诱导型一氧化氮合酶（iNOS）诱导和细胞凋亡的作用独立于核因子κB（NF-κB）的核转位，因为SB203580并不能阻止IL-1β诱导的该转录因子与DNA结合。此外，单独使用SB203580会导致JNK2磷酸化，这可能反映了对p38激活的磷酸酶的抑制。结论是，p38独立于NF-κB转位介导细胞因子诱导的iNOS诱导和细胞凋亡。此外，在胰腺RINm5F细胞中，由于同时激活JNK2，抑制p38对iNOS诱导和细胞凋亡的预防作用可能会部分被掩盖。
