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 A g-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-al pha increases IFNgamma but not LPS-induced NO2- production. Incubation with target oligodendrocytes also increases NO2- production in a cont act-dependent manner. NO2- production is inhibited by NO synthase anta gonists, 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, a nti-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 oligodendr ocyte and possibly play a role in lesion formation in multiple scleros is.