Involvement of mitogen-activated protein kinase homologues in the regulation of lipopolysaccharide-mediated induction of cyclo-oxygenase-2 but not nitric oxide synthase in RAW 264.7 macrophages

Andrew Paul, Ana Cuenda, Clare E. Bryant, Jo Murray, Edwin R. Chilvers, Philip Cohen, Gwyn W. Gould, Robin Plevin

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100 Citations (Scopus)

Abstract

In RAW 264.7 macrophages lipopolysaccharide (LPS) stimulated the activation of p42 and p44 MAP kinases and their upstream activator mitogen-activated protein (MAP) kinase kinase (MAPKK), and induced the 69-kDa isoform of cyclo-oxygenase-2 (COX-2) and the 130-kDa isoform of nitric oxide synthase (iNOS). PD 098059, a specific inhibitor of the activation of MAPKK, prevented LPS-mediated activation of MAPKK IC50 = 3.0 ± 0.1 μM, n = 3 and p42/44 MAP kinases and substantially reduced the induction of COX-2 by approximately 40%-70%, but was without effect upon the induction of iNOS. In parallel, LPS also stimulated the activation of p38 MAP kinase and the MAPKAP kinase-2, a downstream target of p38 MAP kinase. SB 203580, a specific inhibitor of p38 MAP kinase prevented the activation of p38 MAP kinase IC50 = 3.3 ± 1.4 μM, n = 3 and MAPKAP kinase-2 by LPS and reduced the induction of COX-2 by approximately 50-90%, with no significant effect upon iNOS expression. These studies indicate the involvement of both the classical p42/44 MAP kinases and p38 MAP kinase in the regulation of COX-2 but not iNOS induction following exposure to LPS. Copyright (C) 1999 Elsevier Science Inc.

Original languageEnglish
Pages (from-to)491-497
Number of pages7
JournalCellular Signalling
Volume11
Issue number7
DOIs
Publication statusPublished - 1 Jul 1999

Keywords

  • COX-2
  • iNOS
  • lipopolysaccharide
  • MAP kinase
  • PD 098059
  • SB 203580
  • mitogen activated protein kinase
  • nitric oxide synthase
  • enzyme activation

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