Tags

Type your tag names separated by a space and hit enter

Dipyridamole activation of mitogen-activated protein kinase phosphatase-1 mediates inhibition of lipopolysaccharide-induced cyclooxygenase-2 expression in RAW 264.7 cells.
Eur J Pharmacol 2006; 541(3):138-46EJ

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-kappaB) signaling pathway as demonstrated by inhibition of the inhibitor of NF-kappaB (IkappaB) phosphorylation, IkappaB 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 IkappaB kinase-beta (IKK-beta) activities in RAW 264.7 cells. A p38 MAPK inhibitor, SB 203580, inhibited LPS-stimulated COX-2 expression and IKK-beta activation suggesting that LPS may activate the NF-kappaB 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-beta activation and subsequently the NF-kappaB signaling pathway that mediates LPS-induced cyclooxygenase-2 expression in RAW 264.7 cells.

Authors+Show Affiliations

Department of Internal Medicine, Taipei Medical University, Wan-Fang Hospital, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16765938

Citation

Chen, Tso-Hsiao, et al. "Dipyridamole Activation of Mitogen-activated Protein Kinase Phosphatase-1 Mediates Inhibition of Lipopolysaccharide-induced Cyclooxygenase-2 Expression in RAW 264.7 Cells." European Journal of Pharmacology, vol. 541, no. 3, 2006, pp. 138-46.
Chen TH, Kao YC, Chen BC, et al. Dipyridamole activation of mitogen-activated protein kinase phosphatase-1 mediates inhibition of lipopolysaccharide-induced cyclooxygenase-2 expression in RAW 264.7 cells. Eur J Pharmacol. 2006;541(3):138-46.
Chen, T. H., Kao, Y. C., Chen, B. C., Chen, C. H., Chan, P., & Lee, H. M. (2006). Dipyridamole activation of mitogen-activated protein kinase phosphatase-1 mediates inhibition of lipopolysaccharide-induced cyclooxygenase-2 expression in RAW 264.7 cells. European Journal of Pharmacology, 541(3), pp. 138-46.
Chen TH, et al. Dipyridamole Activation of Mitogen-activated Protein Kinase Phosphatase-1 Mediates Inhibition of Lipopolysaccharide-induced Cyclooxygenase-2 Expression in RAW 264.7 Cells. Eur J Pharmacol. 2006 Jul 17;541(3):138-46. PubMed PMID: 16765938.
* Article titles in AMA citation format should be in sentence-case
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-Mo, PY - 2006/01/23/received PY - 2006/05/01/revised PY - 2006/05/08/accepted PY - 2006/6/13/pubmed PY - 2006/9/20/medline PY - 2006/6/13/entrez SP - 138 EP - 46 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 541 IS - 3 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-kappaB) signaling pathway as demonstrated by inhibition of the inhibitor of NF-kappaB (IkappaB) phosphorylation, IkappaB 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 IkappaB kinase-beta (IKK-beta) activities in RAW 264.7 cells. A p38 MAPK inhibitor, SB 203580, inhibited LPS-stimulated COX-2 expression and IKK-beta activation suggesting that LPS may activate the NF-kappaB 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-beta activation and subsequently the NF-kappaB signaling pathway that mediates LPS-induced cyclooxygenase-2 expression in RAW 264.7 cells. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/16765938/Dipyridamole_activation_of_mitogen_activated_protein_kinase_phosphatase_1_mediates_inhibition_of_lipopolysaccharide_induced_cyclooxygenase_2_expression_in_RAW_264_7_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(06)00478-X DB - PRIME DP - Unbound Medicine ER -