Dipyridamole activation of mitogen-activated protein kinase phosphatase-1 mediates inhibition of lipopolysaccharide-induced cyclooxygenase-2 expression in RAW 264.7 cells

Tso Hsiao Chen, Yuan Chung Kao, Bing Chang Chen, Cheng Hsien Chen, Paul Chan, Horng M. Lee

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Dipyridamole is a nucleoside transport inhibitor and a non-selective phosphodiesterase inhibitor. However, the mechanisms by which dipyridamole exerts its anti-inflammatory effects are not completely understood. In the present study, we investigated the role of mitogen-activated kinase phosphatase-1 (MKP-1) in dipyridamole's anti-inflammatory effects. We show that dipyridamole inhibited interleukin-6 and monocyte chemoattractant protein-1 secretion, inducible nitric oxide synthase protein expression, nitrite accumulation, and cyclooxygenase-2 (COX-2) induction in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Dipyridamole inhibited the nuclear factor kappa B (NF-κB) signaling pathway as demonstrated by inhibition of the inhibitor of NF-κB (IκB) phosphorylation, IκB degradation, p65 translocation from the cytosol to the nucleus, and transcription of the reporter gene. Dipyridamole also inhibited LPS-stimulated p38 mitogen-activated protein kinase (p38 MAPK) and IκB kinase-beta (IKK-β) activities in RAW 264.7 cells. A p38 MAPK inhibitor, SB 203580, inhibited LPS-stimulated COX-2 expression and IKK-β activation suggesting that LPS may activate the NF-κB signaling pathway via upstream p38 MAPK activation. Furthermore, dipyridamole stimulated transient activation of MKP-1, a potent inhibitor of p38 MAPK function. Knockdown of MKP-1 by transfecting MKP-1 siRNA or inhibition of MKP-1 by the specific inhibitor, triptolide, significantly reduced the inhibitory effects of dipyridamole on COX-2 expression induced by LPS. Taken together, these data suggest that dipyridamole exerts its anti-inflammatory effect via activation of MKP-1, which dephosphorylates and inactivates p38 MAPK. Inactivation of p38 MAPK in turn inhibits IKK-β activation and subsequently the NF-κB signaling pathway that mediates LPS-induced cyclooxygenase-2 expression in RAW 264.7 cells.

Original languageEnglish
Pages (from-to)138-146
Number of pages9
JournalEuropean Journal of Pharmacology
Volume541
Issue number3
DOIs
Publication statusPublished - Jul 17 2006

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Keywords

  • Anti-inflammatory effect
  • Cyclooxygenase-2
  • Lipopolysaccharide
  • Mitogen-activated kinase phosphatase-1
  • Nitric oxide
  • RAW 264.7 macrophage
  • Signal transduction

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

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