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/macrophages and associated with a so far unknown proteoglycan core protein. Microglial KS-IR is downregulated during T-cell-mediated autoimmune inflammation but largely preserved in degenerative lesion paradigms. This study addresses the role of cytokines and colony-stimulating factors in the regulation of microglial KS-IR. In vitro, ramified microglia in coculture with astrocytes, but not isolated microglia, constitutively expressed KS-IR under control conditions. In both culture paradigms, KS-IR was increased significantly by macrophage- (M-CSF) and granulocyte/macrophage colony-stimulating factors (GM-CSF), as well as tumor necrosis factor-alpha (TNF-alpha). By contrast, the Th1 cytokine interferon-gamma (IFN-gamma) downregulated KS-IR, both when applied 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 from ramified brain microglia. Our data suggest that the expression of microglial KS-IR is under dominant negative control by the Th1 cell cytokine IFN-gamma and represent the first evidence of cytokine-dependent proteoglycan regulation in the CNS.
Jander
S
S
Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany. jander@uni-duesseldorf.de
Schroeter
M
M
Fischer
J
J
Stoll
G
G
D000818:Animals; D000911:Antibodies, Monoclonal; D002478:Cells, Cultured; D018920:Coculture Techniques; D003115:Colony-Stimulating Factors / Q000378:metabolism* / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D007371:Interferon-gamma / Q000008:administration & dosage / Q000378:metabolism; D007632:Keratan Sulfate / Q000378:metabolism*; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000378:metabolism
D000911:Antibodies, Monoclonal; D003115:Colony-Stimulating Factors; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007632:Keratan Sulfate