PMID- 17403137 OWN - NLM STAT- MEDLINE DCOM- 20071015 LR - 20131121 IS - 0022-3042 (Print) IS - 0022-3042 (Linking) VI - 102 IP - 3 DP - 2007 Aug TI - 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. PG - 667-78 AB - 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. FAU - Zhou, Yan AU - Zhou Y AD - Department of Anatomy, Molecular Neurobiology Laboratory, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. FAU - Ling, Eng-Ang AU - Ling EA FAU - Dheen, S Thameem AU - Dheen ST LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20070402 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Anti-Inflammatory Agents) RN - 0 (Ccl2 protein, rat) RN - 0 (Cell Cycle Proteins) RN - 0 (Chemokine CCL2) RN - 0 (Immediate-Early Proteins) RN - 7S5I7G3JQL (Dexamethasone) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 3.1.3.16 (Phosphoprotein Phosphatases) RN - EC 3.1.3.16 (Protein Phosphatase 1) RN - EC 3.1.3.48 (Dual Specificity Phosphatase 1) RN - EC 3.1.3.48 (Dusp1 protein, rat) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatases) SB - IM MH - Animals MH - Anti-Inflammatory Agents/pharmacology MH - Brain/drug effects/immunology/physiopathology MH - Cell Cycle Proteins/drug effects/metabolism MH - Cell Movement/drug effects/immunology MH - Cells, Cultured MH - Chemokine CCL2/*antagonists & inhibitors/metabolism MH - Chemotaxis/drug effects/immunology MH - Coculture Techniques MH - Dexamethasone/*pharmacology MH - Down-Regulation/drug effects/physiology MH - Dual Specificity Phosphatase 1 MH - Encephalitis/*drug therapy/immunology/physiopathology MH - Immediate-Early Proteins/drug effects/metabolism MH - JNK Mitogen-Activated Protein Kinases/metabolism MH - MAP Kinase Signaling System/*drug effects/immunology MH - Microglia/*drug effects/*enzymology/immunology MH - Phosphoprotein Phosphatases/drug effects/metabolism MH - Protein Phosphatase 1 MH - Protein Tyrosine Phosphatases/drug effects/metabolism MH - Rats MH - Rats, Wistar MH - Treatment Outcome MH - p38 Mitogen-Activated Protein Kinases/metabolism EDAT- 2007/04/04 09:00 MHDA- 2007/10/16 09:00 CRDT- 2007/04/04 09:00 PHST- 2007/04/04 09:00 [pubmed] PHST- 2007/10/16 09:00 [medline] PHST- 2007/04/04 09:00 [entrez] AID - JNC4535 [pii] AID - 10.1111/j.1471-4159.2007.04535.x [doi] PST - ppublish SO - J Neurochem. 2007 Aug;102(3):667-78. doi: 10.1111/j.1471-4159.2007.04535.x. Epub 2007 Apr 2.