Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide.
Rat ameboid microglia are able to lyse rat oligodendrocytes in vitro. The lysis is inhibited by transforming growth factor-beta, antagonists of nitric oxide (NO) production, as well as antibodies to TNF-alpha, intercellular adhesion molecule-1 (ICAM-1), and leukocyte functional Ag-1. Ameboid microglial cells spontaneously produce detectable levels of the NO metabolite nitrite (NO2-). Stimuli such as PMA, LPS, and/or IFN-gamma induce micromolar concentrations of NO2- within 24 h. TNF-alpha increases IFN gamma but not LPS-induced NO2- production. Incubation with target oligodendrocytes also increases NO2- production in a contact-dependent manner. NO2- production is inhibited by NO synthase antagonists, transforming growth factor-beta, and anti TNF-alpha. Neither antileukocyte functional Ag-1 nor anti-ICAM-1 inhibit NO2- production by microglia in the presence or absence of oligodendrocytes. Indeed, anti-ICAM-1 treatment increases NO2- production. There is a correlation between ameboid microglial cell killing of oligodendrocytes and NO2- production suggesting NO may be a mechanism of death of the oligodendrocyte and possibly play a role in lesion formation in multiple sclerosis.
Merrill
J E
JE
Department of Neurology, UCLA School of Medicine 90024.
Ignarro
L J
LJ
Sherman
M P
MP
Melinek
J
J
Lane
T E
TE
D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000276:immunology*; D009569:Nitric Oxide / Q000378:metabolism*; D009836:Oligodendroglia / Q000276:immunology*; D051381:Rats; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D015815:Cell Adhesion Molecules; D016169:Lymphocyte Function-Associated Antigen-1; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide