Human Immunodeficiency Virus Type 1 Envelope Glycoprotein gp120 Induces Tumor Necrosis Factora in Astrocytes

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Abstract
Gp120 induction of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) was studied in cultures of purified astrocytes. Incubation of pure mouse cortical astrocytes with gp120 IIIB induced the expression of TNF-alpha mRNA, assessed by in situ hybridization. Anti- TNF-alpha immunocytochemical staining of gp120 IIIB stimulated astrocytes indicated the presence of TNF-alpha. gp120 IIIB treatment also stimulated secretion of bioactive TNF-alpha from astrocytes, which was prevented by inhibitors of transcription and translation. Hippocampal and cerebellar astrocytes displayed similar behaviors. Further, gp120 displayed cytotoxicity for astrocytes that depended on macromolecular synthesis. The data are the first to show gp120 IIIB induction of de novo TNF-alpha production by pure astrocytes. Because TNF-alpha exerts a wide array of effects in the brain of infected individuals and has HIV-1 inducing activity as well, induction of this cytokine by gp120 IIIB in astrocytes may contribute importantly to the pathogenesis of AIDS dementia complex. Since TNF-alpha can stimulate astrocyte reactivity and proliferation by an autocrine mechanism, the extent of the gp120 effect could conceivably increase with HIV-1 disease progression in a self-amplifying loop, involving other cell types, thus favoring both virus persistence and a chronic disease state.