Thrombin induces suppressor of cytokine signaling 3 expression in brain microglia via protein kinase Cdelta activation.

Abstract

Microglia (brain macrophages) are activated upon brain damage. In this study, we demonstrated that thrombin, a pro-inflammatory stimulator of microglia, induced expression of suppressors of cytokine signaling (SOCS) in microglia. RT-PCR analysis and Northern blot analysis showed that thrombin induced SOCS3 mRNA expression. Further experiments indicated SOCS3 expression was not affected by cycloheximide, indicating thrombin directly stimulated SOCS3 transcript expression without de novo protein synthesis. We investigated whether PKCdelta played a role in thrombin-stimulated SOCS3 expression. We found that thrombin activated PKCdelta, and the specific inhibitor of PKCdelta, rottlerin, significantly suppressed thrombin-stimulated SOCS3 expression. In thrombin-pretreated cells, microglial activation-induced by another inflammatory stimulator, lipopolysaccharide, was attenuated compared to that in non-pretreated cells. These results suggest thrombin induce not only proinflammatory mediators but also negative feedback regulators of inflammation, SOCS, which prevent prolonged inflammatory reactions in microglia.