Differential regulation of microglial keratan sulfate immunoreactivity by proinflammatory cytokines and colony-stimulating factors

Resident microglia of the rat CNS express a unique type of keratan sulfate immunoreactivity (KS-IR) that is lacking on peripheral monocytes/macrophage s and associated with a so far unknown proteoglycan core protein. Microglia l KS-IR is downregulated during T-cell-mediated autoimmune inflammation but largely preserved in degenerative lesion paradigms. This study addresses t he role of cytokines and colony-stimulating factors in the regulation of mi croglial KS-IR. In vitro, ramified microglia in coculture with astrocytes, but not isolated microglia, constitutively expressed KS-IR under control co nditions. In both culture paradigms, KS-IR was increased significantly by m acrophage- (M-CSF) and granulocyte/macrophage colony-stimulating factors (G MCSF), as well as tumor necrosis factor-alpha (TNF-alpha). By contrast, the Th1 cytokine interferon-gamma (IFN-gamma) downregulated KS-IR, both when a pplied alone or in combination with either GM-CSF, M-CSF, or TNF-alpha. In vivo, the intracerebroventricular administration of IFN-gamma, but not TNF- alpha, to healthy rats led to an almost complete disappearance of KS-IR fro m ramified brain microglia. Our data suggest that the expression of microgl ial KS-IR is under dominant negative control by the Th1 cell cytokine IFN-g amma and represent the first evidence of cytokine-dependent proteoglycan re gulation in the CNS. (C) 2000 Wiley-Liss, Inc.