Molecular Mechanisms of Microglial Deactivation by TGF-β-inducible Protein βig-h3

摘要

βig-h3 is a secretory protein that is induced by TGF-β and implicated in various disease conditions including fibrosis. We have previously reported that βig-h3 expression is implicated in astrocyte response to brain injury. In this study, we further investigated potential roles of βig-h3 protein in the injured central nervous system (CNS). We specifically assessed whether the treatment of microglial cells with βig-h3 can regulate microglial activity. Microglial cells are the prime effector cellsin CNS immune and inflammatory responses. When activated, they produce a number of inflammatory mediators, which can promote neuronal injury. We prepared conditioned medium from the stable CHO cell line transfected with human βig-h3 cDNA. We then examined the effects of the conditioned medium on the LPS- or IFN-γ-mediated induction of proinflammatory molecules in microglial cells, Preincubation with the conditioned medium significantly attenuated LPS-mediated upregulation of TNF-α, IL-1β, iNOS andCOX-2 mRNA expression in BV2 murine microglial cells. It also reduced IFN-γ-mediated upregulation of TNF-α and COX-2 mRNA expression but not iNOS mRNA expression. Assays of nitric oxide release correlated with the mRNA data, which showed selective inhibition of LPS-mediated nitric oxide production. Although the regulatory mechanisms need to be further investigated, these results suggest that astrocyte-derived βig-h3 may contribute to protection of the CNS from immune-mediated damage via controlling microglial inflammatory responses.