Cytokine-stimulated, but not HIV-infected, human monocyte-derived macrophages produce neurotoxic levels of L-cysteine

Michael W. Yeh, Marcus Kaul, Jialin C Zheng, Hans S L M Nottet, Michael Thylin, Howard Eliot Gendelman, Stuart A. Lipton

Research output: Contribution to journalArticle

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Abstract

Approximately one-quarter of individuals with AIDS develop neuropathological symptoms that are attributable to infection of the brain with HIV. The cognitive manifestations have been termed HIV-associated dementia. The mechanisms underlying HIV-associated neuronal injury are incompletely understood, but various studies have confirmed the release of neurotoxins by macrophages/microglia infected with HIV-1 or stimulated by viral proteins, including the envelope glycoprotein gp120. In the present study, we investigated the possibility that L-cysteine, a neurotoxin acting at the N-methyl-D-asparate subtype of glutamate receptor, could contribute to HIV-associated neuronal injury. Picomolar concentrations of gp120 were found to stimulate cysteine release from human monocyte-derived macrophages (hMDM) in amounts sufficient to injure cultured rat cerebrocortical neurons. TNF-α and IL-1β, known to be increased in HIV-encephalitic brains, as well as a cellular product of cytokine stimulation, ceramide, were also shown to induce release of cysteine from hMDM in a dose-dependent manner. A TNF-α- neutralizing Ab and an IL-11βR antagonist partially blocked gp120-induced cysteine release, suggesting that these cytokines may mediate the actions of gp120. Interestingly, hMDM infected with HIV-1 produced significantly less cysteine than uninfected cells following stimulation with TNF-α. Our findings imply that cysteine may play a role in the pathogenesis of neuronal injury in HIV-associated dementia due to its release from immune-activated macrophages but not virus-infected macrophages. Such uninfected cells comprise the vast majority of mononuclear phagocytes (macrophages and microglia) found in HIV-encephalitic brains.

Original languageEnglish (US)
Pages (from-to)4265-4270
Number of pages6
JournalJournal of Immunology
Volume164
Issue number8
DOIs
StatePublished - Apr 15 2000

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Cysteine
Macrophages
HIV
Cytokines
AIDS Dementia Complex
Neurotoxins
Microglia
HIV-1
Wounds and Injuries
Brain
Viral Envelope Proteins
Neurobehavioral Manifestations
Ceramides
Glutamate Receptors
Phagocytes
Interleukin-1
Glycoproteins
Acquired Immunodeficiency Syndrome
Viruses
Neurons

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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Cytokine-stimulated, but not HIV-infected, human monocyte-derived macrophages produce neurotoxic levels of L-cysteine. / Yeh, Michael W.; Kaul, Marcus; Zheng, Jialin C; Nottet, Hans S L M; Thylin, Michael; Gendelman, Howard Eliot; Lipton, Stuart A.

In: Journal of Immunology, Vol. 164, No. 8, 15.04.2000, p. 4265-4270.

Research output: Contribution to journalArticle

Yeh, Michael W. ; Kaul, Marcus ; Zheng, Jialin C ; Nottet, Hans S L M ; Thylin, Michael ; Gendelman, Howard Eliot ; Lipton, Stuart A. / Cytokine-stimulated, but not HIV-infected, human monocyte-derived macrophages produce neurotoxic levels of L-cysteine. In: Journal of Immunology. 2000 ; Vol. 164, No. 8. pp. 4265-4270.
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