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Dexamethasone suppresses monocyte chemoattractant protein-1 production via mitogen activated protein kinase phosphatase-1 dependent inhibition of Jun N-terminal kinase and p38 mitogen-activated protein kinase in activated rat microglia.
J Neurochem. 2007 Aug; 102(3):667-78.JN

Abstract

Microglial cells release monocyte chemoattractant protein-1 (MCP-1) which amplifies the inflammation process by promoting recruitment of macrophages and microglia to inflammatory sites in several neurological diseases. In the present study, dexamethasone (Dex), an anti-inflammatory and immunosuppressive drug has been shown to suppress the mRNA and protein expression of MCP-1 in activated microglia resulting in inhibition of microglial migration. This has been further confirmed by the chemotaxis assay which showed that Dex or MCP-1 neutralization with its antibody inhibits the microglial recruitment towards the conditioned medium of lipopolysaccharide (LPS)-treated microglial culture. This study also revealed that the down-regulation of the MCP-1 mRNA expression by Dex in activated microglial cells was mediated via mitogen-activated protein kinase (MAPK) pathways. It has been demonstrated that Dex inhibited the phosphorylation of Jun N-terminal kinase (JNK) and p38 MAP kinases as well as c-jun, the JNK substrate in microglia treated with LPS. The involvement of JNK and p38 MAPK pathways in induction of MCP-1 production in activated microglial cells was confirmed as there was an attenuation of MCP-1 protein release when microglial cells were treated with inhibitors of JNK and p38. In addition, Dex induced the expression of MAP kinase phosphatase-1 (MKP-1), the negative regulator of JNK and p38 MAP kinases in microglial cells exposed to LPS. Blockade of MKP-1 expression by triptolide enhanced the phosphorylation of JNK and p38 MAPK pathways and the mRNA expression of MCP-1 in activated microglial cells treated with Dex. In summary, Dex inhibits the MCP-1 production and subsequent microglial cells migration to the inflammatory site by regulating MKP-1 expression and the p38 and JNK MAPK pathways. This study reveals that the MKP-1 and MCP-1 as novel mediators of biological effects of Dex may help developing better therapeutic strategies for the treatment of patients with neuroinflammatory diseases.

Authors+Show Affiliations

Department of Anatomy, Molecular Neurobiology Laboratory, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.No affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

17403137

Citation

Zhou, Yan, et al. "Dexamethasone Suppresses Monocyte Chemoattractant Protein-1 Production Via Mitogen Activated Protein Kinase Phosphatase-1 Dependent Inhibition of Jun N-terminal Kinase and P38 Mitogen-activated Protein Kinase in Activated Rat Microglia." Journal of Neurochemistry, vol. 102, no. 3, 2007, pp. 667-78.
Zhou Y, Ling EA, Dheen ST. Dexamethasone suppresses monocyte chemoattractant protein-1 production via mitogen activated protein kinase phosphatase-1 dependent inhibition of Jun N-terminal kinase and p38 mitogen-activated protein kinase in activated rat microglia. J Neurochem. 2007;102(3):667-78.
Zhou, Y., Ling, E. A., & Dheen, S. T. (2007). Dexamethasone suppresses monocyte chemoattractant protein-1 production via mitogen activated protein kinase phosphatase-1 dependent inhibition of Jun N-terminal kinase and p38 mitogen-activated protein kinase in activated rat microglia. Journal of Neurochemistry, 102(3), 667-78.
Zhou Y, Ling EA, Dheen ST. Dexamethasone Suppresses Monocyte Chemoattractant Protein-1 Production Via Mitogen Activated Protein Kinase Phosphatase-1 Dependent Inhibition of Jun N-terminal Kinase and P38 Mitogen-activated Protein Kinase in Activated Rat Microglia. J Neurochem. 2007;102(3):667-78. PubMed PMID: 17403137.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dexamethasone suppresses monocyte chemoattractant protein-1 production via mitogen activated protein kinase phosphatase-1 dependent inhibition of Jun N-terminal kinase and p38 mitogen-activated protein kinase in activated rat microglia. AU - Zhou,Yan, AU - Ling,Eng-Ang, AU - Dheen,S Thameem, Y1 - 2007/04/02/ PY - 2007/4/4/pubmed PY - 2007/10/16/medline PY - 2007/4/4/entrez SP - 667 EP - 78 JF - Journal of neurochemistry JO - J Neurochem VL - 102 IS - 3 N2 - Microglial cells release monocyte chemoattractant protein-1 (MCP-1) which amplifies the inflammation process by promoting recruitment of macrophages and microglia to inflammatory sites in several neurological diseases. In the present study, dexamethasone (Dex), an anti-inflammatory and immunosuppressive drug has been shown to suppress the mRNA and protein expression of MCP-1 in activated microglia resulting in inhibition of microglial migration. This has been further confirmed by the chemotaxis assay which showed that Dex or MCP-1 neutralization with its antibody inhibits the microglial recruitment towards the conditioned medium of lipopolysaccharide (LPS)-treated microglial culture. This study also revealed that the down-regulation of the MCP-1 mRNA expression by Dex in activated microglial cells was mediated via mitogen-activated protein kinase (MAPK) pathways. It has been demonstrated that Dex inhibited the phosphorylation of Jun N-terminal kinase (JNK) and p38 MAP kinases as well as c-jun, the JNK substrate in microglia treated with LPS. The involvement of JNK and p38 MAPK pathways in induction of MCP-1 production in activated microglial cells was confirmed as there was an attenuation of MCP-1 protein release when microglial cells were treated with inhibitors of JNK and p38. In addition, Dex induced the expression of MAP kinase phosphatase-1 (MKP-1), the negative regulator of JNK and p38 MAP kinases in microglial cells exposed to LPS. Blockade of MKP-1 expression by triptolide enhanced the phosphorylation of JNK and p38 MAPK pathways and the mRNA expression of MCP-1 in activated microglial cells treated with Dex. In summary, Dex inhibits the MCP-1 production and subsequent microglial cells migration to the inflammatory site by regulating MKP-1 expression and the p38 and JNK MAPK pathways. This study reveals that the MKP-1 and MCP-1 as novel mediators of biological effects of Dex may help developing better therapeutic strategies for the treatment of patients with neuroinflammatory diseases. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/17403137/Dexamethasone_suppresses_monocyte_chemoattractant_protein_1_production_via_mitogen_activated_protein_kinase_phosphatase_1_dependent_inhibition_of_Jun_N_terminal_kinase_and_p38_mitogen_activated_protein_kinase_in_activated_rat_microglia_ L2 - https://doi.org/10.1111/j.1471-4159.2007.04535.x DB - PRIME DP - Unbound Medicine ER -