Abstract
HIV-1 Tat protein stimulates the production of both TNF-alpha and IL-10 in human monocytes. Taking into account the ability of TNF-alpha to induce IL-10 production, we evaluated the link between Tat, TNF-alpha and IL-10 and the implication of PKC and p38 MAP kinase pathways. Our data showed that (i) in the presence of neutralizing anti-TNF-alpha antibodies, IL-10 production is only partially inhibited; (ii) in a calcium-free medium, while TNF-alpha production is totally inhibited, Tat continues to induce IL-10; (iii) under these conditions, Tat-mediated IL-10 production is associated with PKC-delta activation; and (iv) downstream of PKC, p38 MAP kinase is crucial for TNF-alpha independent IL10 production. Overall, our data suggest a new mechanism, implicating Tat protein, by which HIV-1 may maintain a constant production of the immunosuppressive IL-10 cytokine, even in the absence of TNF-alpha production. In consequence, HIV-1 may escape immune surveillance and thus promote the establishment of an immunosuppressive state.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Calcium / metabolism
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Enzyme Activation
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Humans
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Interleukin-10 / immunology*
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Isoenzymes / metabolism
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Monocytes / cytology
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Monocytes / immunology*
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / metabolism
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Protein Kinase C beta
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Protein Kinase C-delta / antagonists & inhibitors
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Protein Kinase C-delta / metabolism*
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Signal Transduction / physiology
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Subcellular Fractions / enzymology
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / immunology*
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism*
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tat Gene Products, Human Immunodeficiency Virus / genetics
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tat Gene Products, Human Immunodeficiency Virus / immunology*
Substances
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Isoenzymes
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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tat Gene Products, Human Immunodeficiency Virus
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Interleukin-10
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PRKCD protein, human
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Protein Kinase C
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Protein Kinase C beta
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Protein Kinase C-delta
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p38 Mitogen-Activated Protein Kinases
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Calcium