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 and inflammatory responses by which various inflammatory genes are induced. Although IL-1 signaling is known to involve PI3-kinase, p38 mitogen-activated protein (MAP) kinase and extracellular signal-regulated kinase (ERK), the crosstalk of these kinases on the IL-1-mediated signal transduction is not clear. We used two specific inhibitors, SB203580 which selectively inhibits p38 MAP kinase and LY294002 which inhibits PI3-kinase, respectively, to explore the involvement of these kinases in the IL-1-induced NF-kappa B activation, using a human glioblastoma cell line, T98G. Two kinase inhibitors decreased IL-1-induced IL-8 mRNA and protein levels markedly. IL-1 caused phosphorylation of p38 MAP kinase with concomitant recruitment of PI3-kinase to IL-1 receptor I (IL-1RI) and its activation. In this context, pretreatment of LY294002, but not SB203580, inhibited IL-1-induced NF-kappa B activation significantly. While IL-1 induced-AP-1 activation was moderate, both LY294002 and SB203580 suppressed IL-1-induced AP-1 activation. These observations were prominent particularly in the TRAF6 transfection system, in which overexpression of wild type TRAF6 augmented the IL-1 mediated NF-kappa B and AP-1 activation, while dominant negative TRAF6 construct (delta TRAF6) suppressed these activation. 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-kappa B activation. Above results indicated that both PI3-kinase and p38 MAP kinase are differentially involved in IL-1-induced NF-kappa B and AP-1 activation.
Funakoshi
M
M
Department of Biochemistry, Kyoritsu College of Pharmacy, 1-5-30 Shibakoen, Minato, Tokyo 105-8512, Japan.
Sonoda
Y
Y
Tago
K
K
Tominaga
S
S
Kasahara
T
T
D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D002867:Chromones; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D016209:Interleukin-8; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins; D011725:Pyridines; D048029:TNF Receptor-Associated Factor 6; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093642:SB 203580