Downregulation of transforming growth factor-β2 facilitates inflammation in the central nervous system by reciprocal astrocyte/microglia interactions

The central nervous system is an immune privileged organ in which inflammatory reactions are normally downregulated by mechanisms that are not completely understood. Transforming growth factor (TGF)-beta 2 is constitutively expressed in the adult central nervous system and little is known about its regulation and modulatory role during neuroinflammation. In this study, we show that TGF beta 2 mRNA and protein are downregulated in the acute phase of chronic relapsing experimental autoimmune encephalomyelitis, whereas the homologous cytokine TGF beta 1 is upregulated. To further characterize regulatory mechanisms, we resorted to an in vitro glial cell culture system. The proinflammatory cytokines IFN gamma and TNF alpha suppressed TGF beta 2 secretion by astrocytes, the major intracerebral producers of TGF beta 2. On the cellular level, activated microglia inhibited TGF beta 2 secretion but induced TGF beta 1 through soluble factors. On the other hand, TGF beta 2 influenced antigen-presenting cell functions of microglia by downregulating major histocompatibility complex class II expression and costimulatory/adhesion molecules, and thereby inhibited myelin basic protein-specific T cell proliferation. These data suggest that TGF beta 2 plays a central role in maintenance of the immune privilege of the central nervous system. Downregulation of astrocytic TGF beta 2 by T cell- and microglia-secreted cytokines appears to be a critical step in providing the grounds for acute and chronic neuroinflammation.