Molecular mechanisms of lipopolysaccharide-induced cyclooxygenase-2 expression in human neutrophils: Involvement of the mitogen-activated protein kinase pathway and regulation by anti-inflammatory cytokines

Shuji Nagano, Takeshi Otsuka, Hiroaki Niiro, Kunihiro Yamaoka, Yojirou Arinobu, Eiichi Ogami, Mitsuteru Akahoshi, Yasushi Inoue, Katsuhisa Miyake, Hitoshi Nakashima, Yoshiyuki Niho, Mine Harada

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Neutrophils are an important cellular source of proinflammatory mediators, whose regulation may be of potential benefit for the treatment of a number of inflammatory diseases. However, the mechanisms of lipopolysaccharide (LPS)-induced neutrophil activation and its regulation by anti-inflammatory cytokines have not yet been fully elucidated. Recent studies have revealed that mitogen-activated protein kinases (MAPK) play a crucial role in the generation of proinflammatory mediators in some cell types. Therefore, we conducted this study to determine whether MAPK activation could be involved in prostaglandin E2 (PGE2) production and cyclooxygenase (COX)-2 expression in LPS-stimulated human neutrophils. PD98059 (MEK1 inhibitor) and SB203580 (p38MAPK inhibitor) reduced PGE2 production as well as COX-2 expression in LPS-stimulated neutrophils. In addition, both extracellular signal-regulated protein kinase (ERK) and p38MAPK were phosphorylated and activated in time- and dose-dependent manners. Since we previously showed that IL-10 and IL-4 similarly inhibited COX-2 expression in LPS-stimulated neutrophils, we next tested the effects of IL-10 and IL-4 on the phosphorylation and activation of both kinases. IL-10 inhibited the phosphorylation and activation of p38MAPK, but not ERK. In addition, IL-4 caused a marginal inhibition in the activation of p38MAPK. Taken together, these results suggest that both ERK and p38MAPK pathways are involved in LPS-induced COX-2 expression and PGE2 production in neutrophils, and IL-10 and IL-4 inhibit neutrophil prostanoid synthesis by down-regulating the activation of p38MAPK.

Original languageEnglish
Pages (from-to)733-740
Number of pages8
JournalInternational immunology
Volume14
Issue number7
DOIs
Publication statusPublished - 2002

Keywords

  • Extracellular signal-regulated protein kinase
  • IL-10
  • IL-4
  • In vitro kinase assay
  • Mitogen-activated protein kinase phosphorylation
  • Prostaglandin E
  • p38

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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