title: Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: implications for the neuropathogenesis of HIV disease.
abstract: Human immunodeficiency virus (HIV) infection of brain macrophages and astroglial proliferation are central features of HIV-induced central nervous system (CNS) disorders. These observations suggest that glial cellular interactions participate in disease. In an experimental system to examine this process, we found that cocultures of HIV-infected monocytes and astroglia release high levels of cytokines and arachidonate metabolites leading to neuronotoxicity. HIV-1ADA-infected monocytes cocultured with human glia (astrocytoma, neuroglia, and primary human astrocytes) synthesized tumor necrosis factor (TNF-alpha) and interleukin 1 beta (IL-1 beta) as assayed by coupled reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and biological activity. The cytokine induction was selective, cell specific, and associated with induction of arachidonic acid metabolites. TNF-beta, IL-1 alpha, IL-6, interferon alpha (IFN-alpha), and IFN-gamma were not produced. Leukotriene B4, leukotriene D4, lipoxin A4, and platelet-activating factor were detected in large amounts after high-performance liquid chromatography separation and correlated with cytokine activity. Specific inhibitors of the arachidonic cascade markedly diminished the cytokine response suggesting regulatory relationships between these factors. Cocultures of HIV-infected monocytes and neuroblastoma or endothelial cells, or HIV-infected monocyte fluids, sucrose gradient-concentrated viral particles, and paraformaldehyde-fixed or freeze-thawed HIV-infected monocytes placed onto astroglia failed to induce cytokines and neuronotoxins. This demonstrated that viable monocyte-astroglia interactions were required for the cell reactions. The addition of actinomycin D or cycloheximide to the HIV-infected monocytes before coculture reduced, > 2.5-fold, the levels of TNF-alpha. These results, taken together, suggest that the neuronotoxicity associated with HIV central nervous system disorders is mediated, in part, through cytokines and arachidonic acid metabolites, produced during cell-to-cell interactions between HIV-infected brain macrophages and astrocytes.
authors.affiliation: Department of Cellular Immunology, Walter Reed Army Institute of Research, Washington, DC 20307.
authors.forename: P
authors.initials: P
authors.lastname: Genis
authors.forename: M
authors.initials: M
authors.lastname: Jett
authors.forename: E W
authors.initials: EW
authors.lastname: Bernton
authors.forename: T
authors.initials: T
authors.lastname: Boyle
authors.forename: H A
authors.initials: HA
authors.lastname: Gelbard
authors.forename: K
authors.initials: K
authors.lastname: Dzenko
authors.forename: R W
authors.initials: RW
authors.lastname: Keane
authors.forename: L
authors.initials: L
authors.lastname: Resnick
authors.forename: Y
authors.initials: Y
authors.lastname: Mizrachi
authors.forename: D J
authors.initials: DJ
authors.lastname: Volsky
mesh_terms: D000818:Animals; D016375:Antisense Elements (Genetics); D016718:Arachidonic Acid / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D001932:Brain Neoplasms; D002450:Cell Communication; D002455:Cell Division; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology*; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D015777:Eicosanoids / Q000302:isolation & purification / Q000378:metabolism; D005333:Fetus; D006678:HIV / Q000235:genetics / Q000502:physiology*; D015658:HIV Infections / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008084:Lipoxygenase / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000502:physiology*; D009474:Neurons / Q000166:cytology; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
chemical_list: D016375:Antisense Elements (Genetics); D016207:Cytokines; D015777:Eicosanoids; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D012367:RNA, Viral; D016718:Arachidonic Acid; D003907:Dexamethasone; D008084:Lipoxygenase