title: Suppressive effect of simvastatin on interferon-beta-induced expression of CC chemokine ligand 5 in microglia.
abstract: Despite the pivotal role of microglia in immune system of the brain, a growing body of evidence suggests that the excessive microglial activation provokes neuronal and glial damages, leading to neurodegenerative and neuroinflammatory disorders. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, have recently received much attention for their suppressive effects on inflammation in the central nervous system. In the current study, we have examined the statin-mediated inhibition of microglial function, especially that of chemokine production. Stimulation of microglial cells with interferon-beta (IFN-beta) resulted in the expression of CC chemokine ligand 5 (CCL5), a major chemoattractant of inflammatory cells. Microglial CCL5 response was synergistically potentiated by costimulation with IFN-beta and tumor necrosis factor-alpha (TNF-alpha). The simvastatin treatment significantly diminished the microglial CCL5 expression induced by IFN-beta alone or by IFN-beta/TNF-alpha combination. In the presence of simvastatin, the IFN-beta-induced activation of Janus kinase (Jak)-signal transducer and activator of transcription (STAT) pathway was attenuated, although this compound had little or no effect on the TNF-alpha-evoked activation of nuclear factor kappaB and c-Jun N-terminal kinase pathways. In addition, chemical inhibitor of Jak-STAT signaling significantly diminished the IFN-beta-induced expression of CCL5 in microglia. Taken together, these results suggest that simvastatin suppresses the IFN-beta-induced expression of CCL5 via down-regulation of Jak-STAT signaling pathway.
authors.affiliation: Laboratory of Neurovirology, Department of Virology 1, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku, Tokyo, Japan. nakamich@nih.go.jp
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakamichi
authors.forename: Megumi
authors.initials: M
authors.lastname: Saiki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitani
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kuboyama
authors.forename: Kinjiro
authors.initials: K
authors.lastname: Morimoto
authors.forename: Mutsuyo
authors.initials: M
authors.lastname: Takayama-Ito
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kurane
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D018946:Chemokine CCL5; D019742:Chemokines, CC / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007370:Interferon Type I / Q000494:pharmacology*; D053613:Janus Kinase 1 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C483024:CCL5 protein, human; D018946:Chemokine CCL5; D019742:Chemokines, CC; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007370:Interferon Type I; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014409:Tumor Necrosis Factor-alpha; D019821:Simvastatin; D053613:Janus Kinase 1