title: The effects of the HIV-1 envelope protein gp120 on the production of nitric oxide and proinflammatory cytokines in mixed glial cell cultures.
abstract: 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-alpha, 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-1IIIB and HIV-1SF2, 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-1IIIB gp120 released 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-1SF2 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 IL-6 production, in situ hybridization with mRNA for IL-6 was performed in HIV-1IIIB gp120- or HIV-1SF2 gp120-stimulated microgliaenriched or astrocyte-enriched cultures. HIV-1IIIB gp120 or HIV-1SF2 gp120 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-alpha, IL-1, or IL-6 from glial cells is differentially regulated by HIV-1IIIB gp120 and HIV-1SF2 gp120. 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.
authors.affiliation: Section of Neuropharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors.forename: L Y
authors.initials: LY
authors.lastname: Kong
authors.forename: B C
authors.initials: BC
authors.lastname: Wilson
authors.forename: M K
authors.initials: MK
authors.lastname: McMillian
authors.forename: G
authors.initials: G
authors.lastname: Bing
authors.forename: P M
authors.initials: PM
authors.lastname: Hudson
authors.forename: J S
authors.initials: JS
authors.lastname: Hong
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D015699:HIV Envelope Protein gp120 / Q000276:immunology* / Q000494:pharmacology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D009569:Nitric Oxide / Q000096:biosynthesis*; D009573:Nitrites / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D015699:HIV Envelope Protein gp120; D007375:Interleukin-1; D015850:Interleukin-6; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide