Cytokine-Stimulated, But Not HIV-Infected, Human Monocyte-Derived Macrophages Produce Neurotoxic Levels of L-Cysteine

• Published in: The Journal of immunology (1950) 2000-04, Vol.164 (8), p.4265-4270
• Main Authors: Yeh, Michael W, Kaul, Marcus, Zheng, Jialin, Nottet, Hans S. L. M, Thylin, Michael, Gendelman, Howard E, Lipton, Stuart A
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Cerebral Cortex; cysteine; Cysteine - antagonists & inhibitors; Cysteine - biosynthesis; Cysteine - metabolism; Cysteine - toxicity; Cytokines - physiology; Dose-Response Relationship, Immunologic; HIV Envelope Protein gp120 - physiology; HIV-1 - immunology; Human immunodeficiency virus; Humans; Immune Sera - pharmacology; Interleukin 1 Receptor Antagonist Protein; Interleukin 1^b; Interleukin 1b; Interleukin-1 - metabolism; Interleukin-1 - physiology; Macrophage Activation - immunology; Macrophages - immunology; Macrophages - metabolism; Macrophages - virology; Monocytes - immunology; Monocytes - metabolism; Monocytes - virology; Neurons - drug effects; Neurons - immunology; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-1 - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - physiology; Sialoglycoproteins - pharmacology; Sphingosine - analogs & derivatives; Sphingosine - pharmacology; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.164.8.4265

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 -aspartate 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-alpha and IL-1beta, 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-alpha-neutralizing Ab and an IL-1betaR 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-alpha. 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.