Gp-41-Mediated Astrocyte Inducible Nitric Oxide Synthase mRNA Expression: Involvement of Interleukin-1β Production by Microglia

Abstract

Mechanisms underlying human immunodeficiency virus-1 encephalopathy are not completely known; however, recent studies suggest that the viral protein gp41 may be neurotoxic via activation of inducible nitric oxide synthase (iNOS) in glial cells. In the present study, we investigated the NO-generating activity of primary human fetal astrocytes in response to gp41 and the relationship to microglial cell production of interleukin-1 (IL-1). Gp41 failed to trigger iNOS mRNA expression in highly enriched (>99%) astrocyte or microglial cell cultures. However, gp41-treated microglia released a factor(s) that triggered iNOS mRNA expression and NO production in astrocytes. Because IL-1 receptor antagonist protein blocked gp41-induced NO production, a pivotal role was suggested for microglial cell IL-1 production in astrocyte iNOS expression. Also, gp41 induced IL-1beta mRNA expression and IL-1 production in microglial cell but not astrocyte cultures. Using specific inhibitors, we found that gp41-induced IL-1beta production in microglia was mediated via a signaling pathway involving protein-tyrosine kinase. These data support the hypothesis that gp41 induces astrocyte NO production indirectly by triggering upregulation of microglial cell IL-1 expression.

Tyk2/STAT3 Signaling Mediates β-Amyloid-Induced Neuronal Cell Death: Implications in Alzheimer's Disease

“…The blockade of STAT3 dimerization inhibits the upregulation of iNOS transcript induced by A␤, further supporting the notion that STAT3 transcriptional activity is important for the A␤-induced gene transcription. It is noteworthy that A␤ could stimulate NO production in astrocytes and microglia through induction of iNOS expression (Akama et al, 1998;Hu et al, 1999). Activation of STAT3 may therefore mediate the increase in NO release in neurons of AD brain, which has been suggested to scavenge O 2 Ϫ and concurrently increases the cytotoxic species ONOO Ϫ , which mediates neuronal damage in AD brain (Chabrier et al, 1999).…”

Human Immunodeficiency Virus Type 1 (HIV-1) Tat Induces Nitric-oxide Synthase in Human Astroglia

“…The ability of Tat to induce the production of NO in humanU373MG astroglial cells and primary astroglia suggests that neurons in the vicinity of Tat-activated astroglia in brains of HAD patients could be subjected to NO-induced damage. In vitro iNOS has been shown to be induced in glial cells following exposure to HIV-1 or HIV-1 envelope glycoproteins such as gp120 and gp41 (45)(46)(47). Although earlier studies reported iNOS expression in monocyte-derived macrophages, microglia, and astrocytes (45)(46), more recent studies have demonstrated an inability of macrophages or microglia to express iNOS following stimulation with HIV or gp41 (47) at least in vitro.…”

Molecular and cellular mechanisms of neuronal cell death in HIV dementia

“…However, this neurotoxicity and NO production is most likely an indirect consequence of gp41 exposure. It would appear that a majority of the NO response likely comes from the glial cell populations (Hu et al, 1999;Rostasy et al, 1999). There is some evidence that gp41 might interact directly with neurons and induce a decrease in intracellular glutathione, which in turn adversely affects mitochondrial function (Sung et al, 2001).…”