Cytokine-stimulated, but not HIV-infected, human monocyte-derived macrophages produce neurotoxic levels of l -cysteine.
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.
Yeh
M W
MW
Cerebrovascular and Neuroscience Research Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Kaul
M
M
Zheng
J
J
Nottet
H S
HS
Thylin
M
M
Gendelman
H E
HE
Lipton
S A
SA
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex; D003545:Cysteine / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism / Q000633:toxicity*; D016207:Cytokines / Q000502:physiology*; D004306:Dose-Response Relationship, Immunologic; D015699:HIV Envelope Protein gp120 / Q000502:physiology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism / Q000502:physiology; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D009474:Neurons / Q000187:drug effects* / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D012795:Sialoglycoproteins / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology
D016207:Cytokines; D015699:HIV Envelope Protein gp120; C507763:IL1RN protein, human; D007106:Immune Sera; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; C064769:N-acetylsphingosine; D017472:Receptors, Interleukin-1; D016194:Receptors, N-Methyl-D-Aspartate; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D003545:Cysteine; D013110:Sphingosine