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

Megumi Funakoshi, Yoshiko Sonoda, Kenji Tago, Shin Ichi Tominaga, Tadashi Kasahara

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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-κB 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-κB 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-κB and AP-1 activation, while dominant negative TRAF6 construct (ΔTRAF6) suppressed these activation. Namely, LY294002 inhibited TRAF6-mediated IL-1-induced NF-κB and AP-1 activation markedly, while SB203580 inhibited TRAF6-induced AP-1 activation but not NF-κB activation. Above results indicated that both PI3-kinase and p38 MAP kinase are differentially involved in IL-1-induced NF-κB and AP-1 activation.

Original languageEnglish
Pages (from-to)595-604
Number of pages10
JournalInternational Immunopharmacology
Volume1
Issue number3
DOIs
Publication statusPublished - 2001 Mar 19

Keywords

  • IL-1 signaling
  • PI3-kinase
  • TRAF6
  • p38 MAP kinase

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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