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βig-h3 is a secretory protein that is induced by TGF- and implicated in various disease conditions including fibrosis. We have previously reported that ig-h3 expression is implicated in astrocyte response to brain injury. In this study, we further investigated potential roles of ig-h3 protein in the injured central nervous system (CNS). We specifically assessed whether the treatment of microglial cells with ig-h3 can regulate microglial activity. Microglial cells are the prime effector cells in 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 ig-h3 cDNA. We then examined the effects of the conditioned medium on the LPS- or IFN--mediated induction of proinflammatory molecules in microglial cells. Preincubation with the conditioned medium significantly attenuated LPS-mediated upregulation of TNF-, IL-1, iNOS and COX-2 mRNA expression in BV2 murine microglial cells. It also reduced IFN--mediated upregulation of TNF- 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 ig-h3 may contribute to protection of the CNS from immune-mediated damage via controlling microglial inflammatory responses.