The Effects of the HIV-1 Envelope Protein gp120 on the Production of Nitric Oxide and Proinflammatory Cytokines in Mixed Glial Cell Cultures

Although the neurotoxicity induced by the HIV envelope protein, gp120, has been demonstrated to require the presence of glial cells (microglia/astrocytes), the mechanisms for the gp120-induced neurotoxicity are not well understood. Moreover, the neurotoxic potencies of gp120s obtained from various HIV isolates are different. Since nitric oxide (NO) and proinflammatory cytokines (TNF-α, IL-1, IL-6) produced by glial cells have been involved in the neuropathogenesis of various diseases, this study examined the effects of gp120 obtained from two strains, HIV-1IIIBand HIV-1SF2, of the HIV-1 virus on the production of NO, TNF-α, IL-1α, IL-1β, and IL-6 in murine primary mixed glial cell cultures. The glial cells exposed to HIV-1IIIBgp120 released NO, TNF-α, and IL-6 in a dose-dependent manner, whereas IL-1α and IL-1β were undetectable. The cells exposed to HIV-1SF2gp120 increased the release of IL-6 only. The gp120-induced effects were significantly enhanced by priming glial cells with IFN-γ. To investigate the cellular sources and mechanisms of the gp120-induced IL-6 production,in situhybridization with mRNA for IL-6 was performed in HIV-1IIIBgp120- or HIV-1SF2gp120-stimulated microglia-enriched or astrocyte-enriched cultures. HIV-1IIIBgp120 or HIV-1SF2gp120 induced the expression of IL-6 mRNA in both microglia-enriched and astrocyte-enriched cultures, indicating that both microglia and astrocytes produce IL-6, and that the transcriptional regulation is involved in the gp120-induced IL-6 production. Taken together, these results demonstrate that the production of NO, TNF-α, IL-1, or IL-6 from glial cells is differentially regulated by HIV-1IIIBgp120 and HIV-1SF2gp120. These results may provide insights into the roles of NO and proinflammatory cytokines in the neurotoxicity of gp120s and the neuropathology of different strains of HIV-1 viruses.