Abstract
Variety of HIV-1 viral proteins including HIV-1 Nef are known to activate astrocytes and microglia in the brain and cause the release of pro-inflammatory cytokines, which is thought to be one of the mechanisms leading to HIV-1- mediated neurotoxicity. IL-6 and IL-8 have been found in the CSF of patients with HIV-1 associated dementia (HAD), suggesting that they might play important roles in HIV-1 neuropathology. In the present study we examined the effects of HIV-1 Nef on IL-6 and IL-8 induction in astrocytes. The results demonstrate that both IL-6 and IL-8 are significantly induced in HIV-1 Nef-transfected SVGA astrocytes and HIV-1 Nef-treated primary fetal astrocytes. We also determined the molecular mechanisms responsible for the HIV-1 Nef-induced increased IL-6 and IL-8 by using chemical inhibitors and siRNAs against PI3K/Akt/PKC, p38 MAPK, NF-κB, CEBP and AP-1. Our results clearly demonstrate that the PI3K/PKC, p38 MAPK, NF-κB and AP-1 pathways are involved in HIV-1 Nef-induced IL-6 production in astrocytes, while PI3K/PKC and NF-κB pathways are involved in HIV-1 Nef-induced IL-8 production. These results offer new potential targets to develop therapeutic strategy for treatment of HIV-1 associated neurological disorders, prevalent in > 40% of individuals infected with HIV-1.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Astrocytes / drug effects
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Astrocytes / metabolism*
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Astrocytes / pathology
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CCAAT-Enhancer-Binding Proteins / antagonists & inhibitors
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CCAAT-Enhancer-Binding Proteins / genetics
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CCAAT-Enhancer-Binding Proteins / metabolism
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Cell Line
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Fetus
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Gene Expression Regulation
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HIV-1 / chemistry*
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Humans
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Interleukin-6 / biosynthesis
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Interleukin-6 / genetics*
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Interleukin-8 / biosynthesis
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Interleukin-8 / genetics*
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Primary Cell Culture
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / genetics
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Protein Kinase C / metabolism
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction*
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Transcription Factor AP-1 / antagonists & inhibitors
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Transcription Factor AP-1 / genetics
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Transcription Factor AP-1 / metabolism
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Transfection
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nef Gene Products, Human Immunodeficiency Virus / genetics*
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nef Gene Products, Human Immunodeficiency Virus / metabolism
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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CCAAT-Enhancer-Binding Proteins
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CEBPA protein, human
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IL6 protein, human
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Interleukin-6
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Interleukin-8
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NF-kappa B
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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RNA, Small Interfering
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Transcription Factor AP-1
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nef Gene Products, Human Immunodeficiency Virus
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nef protein, Human immunodeficiency virus 1
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Proto-Oncogene Proteins c-akt
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Protein Kinase C
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p38 Mitogen-Activated Protein Kinases