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 (microgl ia/astrocytes), the mechanisms for the gp120-induced neurotoxicity are not well understood. Moreover, the neurotoxic potencies of gp120s obt ained from various HIV isolates are different. Since nitric oxide (NO) and proinflammatory cytokines (TNF-alpha, IL-1, IL-6) produced by gli al cells have been involved in the neuropathogenesis of various diseas es, this study examined the effects of gp120 obtained from two strains , HIV-1(IIIB) and HIV-1(SF2), of the HIV-1 virus on the production of NO, TNF-alpha, IL-1 alpha, IL-1 beta, and IL-6 in murine primary mixed glial cell cultures. The glial cells exposed to HIV-1(IIIB) gp120 rel eased NO, TNF-alpha, and IL-6 in a dose-dependent manner, whereas IL-1 alpha and IL-1 beta were undetectable. The cells exposed to HIV-1(SF2 ) gp120 increased the release of IL-6 only. The gp120-induced effects were significantly enhanced by priming glial cells with IFN-gamma. To investigate the cellular sources and mechanisms of the gp120-induced I L-6 production, in situ hybridization with mRNA for IL-6 was performed in HIV-1(IIIB) gp120- or HIV-1(SF2) gp120-stimulated microglia-enrich ed or astrocyte-enriched cultures. HIV-1(IIIB) gp120 or HIV-1(SF2) gp1 20 induced the expression of IL-6 mRNA in both microglia-enriched and astrocyte-enriched cultures, indicating that both microglia and astroc ytes produce IL-6, and that the transcriptional regulation is involved in the gp120-induced IL-6 production. Taken together, these results d emonstrate that the production of NO, TNF-alpha, IL-1, or IL-6 from gl ial cells is differentially regulated by HIV-1(IIIB) gp120 and HIV-1(S F2) gp120. These results may provide insights into the roles of NO and proinflammatory cytokines in the neurotoxicity of gp120s and the neur opathology of different strains of HIV-1 viruses. (C) 1996 Academic Pr ess, Inc.