ABSTRACT
The response of glial cells to the acute intracerebroventricular administration of interferon-gamma, and of this cytokine combined with the endotoxin lipopolysaccharide or with tumor necrosis factor-alpha, was investigated in the brain of adult mice over a time course of 1 week. Oligodendrocytes were identified by immunocytochemistry, using O4 to label their precursors and 2',3'-cyclic nucleotide 3'-phosphohydrolase as marker of mature cells. Astrocytes were labeled by glial fibrillary acidic protein immunoreactivity and microglial cells by tomato lectin histochemistry. Compared with ovalbumin-injected control cases, all cytokine treatments caused a marked decrease of immunostained mature oligodendrocytes in the brain since 1 day postinjection. O4+ oligodendrocyte precursors increased instead progressively from 2 to 7 days. Astrocytes, markedly activated by cytokine treatments, also exhibited a progressive quantitative increase from 2 days onward. Activation and proliferation of microglial cells were instead most evident at 24 h postinjection. Such glial responses to interferon-gamma injections were especially marked in the periventricular brain parenchyma and were enhanced by coadministration of lipopolysaccharide or tumor necrosis factor-alpha. The findings show that a pulse of proinflammatory mediators in the cerebrospinal fluid affects mature oligodendrocytes, concomitantly with the early appearance of activated microglia, and that such reactions are rapidly followed by an increase of oligodendrocyte precursors paralleled by astrocytic activation. The data, which allowed dissecting the events elicited in glial cell populations by inflammatory mediators via the cerebrospinal fluid, indicate that these molecules elicit in vivo a toxic effect on mature oligodendrocytes and a stimulation of their precursors in the adult brain.
