Differential involvement of p38 mitogen-activated protein kinase and phosphatidyl inositol 3-kinase in the IL-1-mediated NF-kappa B and AP-1 activation

Interleukin-1 (IL-1) is a central regulator of the immune acid inflammatory responses by which various inflammatory genes are induced. Although IL-1 s ignaling is known to involve PI3-kinase. p38 mitogen-activated protein (MAP ) kinase and extracellular signal-regulated kinase (ERK), the crosstalk of their kinases on the IL-1-mediated signal transduction is not clear. We use d two specific inhibitors. SB203580 which selectively inhibits p38 MAP kina se and LY294002 which inhibits PI3-kinase. respectively, to explore the inv olvement of these kinases in the IL-1-induced NF-kappaB activation, using a human glioblastoma cell line, T98G. Two kinase inhibitors decreased IL-1-i nduced IL-8 mRNA and protein levels markedly. IL-1 caused phosphorylation o f p38 MAP kinase with concomitant recruitment of PIS-kinase to IL-1 recepto r I (IL-IRI) and its activation. In this content, pretreatment of LY294002, but not SB203580. inhibited IL-1-induced NF-kappaB activation significantl y. While IL-1 induced-AP-1 activation was moderate. both LY294002 and S8103 580 suppressed IL-1-induced AP-1 activation. These observations were promin ent particularly in the TRAF6 transfection system, in which overexpression of wild type TRAF6 augmented the IL-1 mediated NF-kappaB and AP-1 activatio n, while dominant negative TRAF6 construct (Delta TRAF6) suppressed these a ctivation. Namely. LY294002, inhibited TRAF6-mediated IL-1-induced NF-kappa B and AP-1 activation markedly. while SB203580 inhibited TRAF6-induced AP-1 activation but not NF-kappaB activation. Above results indicated that both PI3-kinase and p38 MAP kinase: are differentially involved in IL-1-induced NF-kappaB and AP-1 activation. (C) 2001 Elsevier Science B.V. All rights r eserved.