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

Research output: Contribution to journalArticle

40 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

Fingerprint

Mitogen-Activated Protein Kinase Phosphatases
Dual Specificity Phosphatase 1
Dipyridamole
Cyclooxygenase 2
Lipopolysaccharides
p38 Mitogen-Activated Protein Kinases
Mitogens
NF-kappa B
Anti-Inflammatory Agents
Protein Kinase Inhibitors
Phosphotransferases
I-kappa B Kinase
RAW 264.7 Cells
Phosphodiesterase Inhibitors
Chemokine CCL2
Nitric Oxide Synthase Type II
Nitrites
Reporter Genes
Nucleosides
Cytosol

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

Cite this

@article{21935a88cf8d4471b2c09a55e1e1bf4f,
title = "Dipyridamole activation of mitogen-activated protein kinase phosphatase-1 mediates inhibition of lipopolysaccharide-induced cyclooxygenase-2 expression in RAW 264.7 cells",
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.",
keywords = "Anti-inflammatory effect, Cyclooxygenase-2, Lipopolysaccharide, Mitogen-activated kinase phosphatase-1, Nitric oxide, RAW 264.7 macrophage, Signal transduction",
author = "Chen, {Tso Hsiao} and Kao, {Yuan Chung} and Chen, {Bing Chang} and Chen, {Cheng Hsien} and Paul Chan and Lee, {Horng M.}",
year = "2006",
month = "7",
day = "17",
doi = "10.1016/j.ejphar.2006.05.002",
language = "English",
volume = "541",
pages = "138--146",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
publisher = "Elsevier",
number = "3",

}

TY - JOUR

T1 - Dipyridamole activation of mitogen-activated protein kinase phosphatase-1 mediates inhibition of lipopolysaccharide-induced cyclooxygenase-2 expression in RAW 264.7 cells

AU - Chen, Tso Hsiao

AU - Kao, Yuan Chung

AU - Chen, Bing Chang

AU - Chen, Cheng Hsien

AU - Chan, Paul

AU - Lee, Horng M.

PY - 2006/7/17

Y1 - 2006/7/17

N2 - 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.

AB - 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.

KW - Anti-inflammatory effect

KW - Cyclooxygenase-2

KW - Lipopolysaccharide

KW - Mitogen-activated kinase phosphatase-1

KW - Nitric oxide

KW - RAW 264.7 macrophage

KW - Signal transduction

UR - http://www.scopus.com/inward/record.url?scp=33745127751&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745127751&partnerID=8YFLogxK

U2 - 10.1016/j.ejphar.2006.05.002

DO - 10.1016/j.ejphar.2006.05.002

M3 - Article

C2 - 16765938

AN - SCOPUS:33745127751

VL - 541

SP - 138

EP - 146

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

IS - 3

ER -