HIV-1 Tat protein induces TNF-alpha and IL-10 production by human macrophages: differential implication of PKC-betaII and -delta isozymes and MAP kinases ERK1/2 and p38.
In this study, we demonstrate that HIV-1 Tat protein is able to induce IL-10 and TNF-alpha in human macrophages. We show that N-terminal Tat 1-45 fragment initiates the PKC pathway by acting at the membrane. Inhibition of PKC pathway, by chemical inhibitors or after PMA treatment, abolishes both IL-10 and TNF-alpha production. Among the eight PKC isoforms present in macrophages, we show that only PKC-betaIotaIota and -delta are activated by Tat or Tat 1-45 in human macrophages. However, their selective inhibition affects only IL-10 production. Downstream of PKC, Tat activates the MAP kinases p38 and ERK1/2 and the transcription factor NF-kappaB. Using chemical inhibitors we show that (i) both ERK1/2 MAP kinase and NF-kappaB transcription factor play an important role in IL-10 and TNF-alpha production, in macrophages stimulated by Tat. However, p38 MAP kinase seems to be involved only in IL-10 and not TNF-alpha production.
Leghmari
Kaoutar
K
Laboratoire d'Immuno-Virologie des Lentivirus des Primates, Université Paul Sabatier 118, Toulouse, France.
Contreras
Xavier
X
Moureau
Corinne
C
Bahraoui
Elmostafa
E
D015153:Blotting, Western; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis*; D007527:Isoenzymes / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000276:immunology / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000276:immunology / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology* / Q000378:metabolism; D011493:Protein Kinase C / Q000276:immunology* / Q000378:metabolism; D064546:Protein Kinase C beta; D051745:Protein Kinase C-delta / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D014409:Tumor Necrosis Factor-alpha; D054322:tat Gene Products, Human Immunodeficiency Virus; D016753:Interleukin-10; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051745:Protein Kinase C-delta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases