Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: Implications for the neuropathogenesis of HIV disease

Peter Genis, Marti Jett, Edward W. Bernton, Thomas Boyle, Harris A. Gelbard, Kirk Dzenko, Robert Keane, Lionel Resnick, Yaffa Mizrachi, David J. Volsky, Leon G. Epstein, Howard E. Gendelman

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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-α) and interleukin 1β (IL-1β) 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-β, IL-1α, IL-6, interferon α. (IFN-α), and IFN-γ 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-α. 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.

Original languageEnglish
Pages (from-to)1703-1718
Number of pages16
JournalJournal of Experimental Medicine
Volume176
Issue number6
StatePublished - Dec 1 1992

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Virus Diseases
Astrocytes
Macrophages
HIV
Cytokines
Monocytes
Coculture Techniques
Neuroglia
Tumor Necrosis Factor-alpha
Central Nervous System Diseases
Interleukin-1
Arachidonic Acid
Leukotriene D4
Leukotriene B4
Platelet Activating Factor
Astrocytoma
Brain
Dactinomycin
Cycloheximide
Neuroblastoma

ASJC Scopus subject areas

  • Immunology

Cite this

Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions : Implications for the neuropathogenesis of HIV disease. / Genis, Peter; Jett, Marti; Bernton, Edward W.; Boyle, Thomas; Gelbard, Harris A.; Dzenko, Kirk; Keane, Robert; Resnick, Lionel; Mizrachi, Yaffa; Volsky, David J.; Epstein, Leon G.; Gendelman, Howard E.

In: Journal of Experimental Medicine, Vol. 176, No. 6, 01.12.1992, p. 1703-1718.

Research output: Contribution to journalArticle

Genis, P, Jett, M, Bernton, EW, Boyle, T, Gelbard, HA, Dzenko, K, Keane, R, Resnick, L, Mizrachi, Y, Volsky, DJ, Epstein, LG & Gendelman, HE 1992, 'Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: Implications for the neuropathogenesis of HIV disease', Journal of Experimental Medicine, vol. 176, no. 6, pp. 1703-1718.
Genis, Peter ; Jett, Marti ; Bernton, Edward W. ; Boyle, Thomas ; Gelbard, Harris A. ; Dzenko, Kirk ; Keane, Robert ; Resnick, Lionel ; Mizrachi, Yaffa ; Volsky, David J. ; Epstein, Leon G. ; Gendelman, Howard E. / Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions : Implications for the neuropathogenesis of HIV disease. In: Journal of Experimental Medicine. 1992 ; Vol. 176, No. 6. pp. 1703-1718.
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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-α) and interleukin 1β (IL-1β) 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-β, IL-1α, IL-6, interferon α. (IFN-α), and IFN-γ 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-α. 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.",
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AU - Boyle, Thomas

AU - Gelbard, Harris A.

AU - Dzenko, Kirk

AU - Keane, Robert

AU - Resnick, Lionel

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