Suppressive effect of simvastatin on interferon-β-induced expression of CC chemokine ligand 5 in microglia

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-β (IFN-β) 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-β and tumor necrosis factor-α (TNF-α). The simvastatin treatment significantly diminished the microglial CCL5 expression induced by IFN-β alone or by IFN-β/TNF-α combination. In the presence of simvastatin, the IFN-β-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-α-evoked activation of nuclear factor κB and c-Jun N-terminal kinase pathways. In addition, chemical inhibitor of Jak-STAT signaling significantly diminished the IFN-β-induced expression of CCL5 in microglia. Taken together, these results suggest that simvastatin suppresses the IFN-β-induced expression of CCL5 via down-regulation of Jak-STAT signaling pathway.