Gp-41-mediated astrocyte inducible nitric oxide synthase mRNA expression: involvement of interleukin-1beta production by microglia.
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.
Institute for Brain and Immune Disorders, Minneapolis Medical Research Foundation and the University of Minnesota Medical School, Minneapolis, Minnesota 55404, USA.
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Hu
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Ali
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Ehrlich
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Peterson
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Chao
D001253:Astrocytes / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis*; D008562:Membrane Glycoproteins / Q000494:pharmacology / Q000502:physiology*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000378:metabolism*
D007375:Interleukin-1; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C053512:glycoprotein 41; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II