Tat protein of human immunodeficiency virus type 1 induces interleukin-10 in human peripheral blood monocytes: implication of protein kinase C-dependent pathway.
The clinical manifestations observed in human immunodeficiency virus type 1 (HIV-1)-infected patients are primarily due to the capacity of the virus and its components to inactivate the immune system. HIV-1 Tat protein could participate in this immune system disorder. This protein is secreted by infected cells of HIV-infected patients and is free in the plasma, where it can interact and be taken up by both infected and noninfected cells. In asymptomatic patients infected by HIV-1, production of interleukin-10 (IL-10), a highly immunosuppressive cytokine, is associated with disease progression to AIDS. In the present work, we tested the capacity of Tat to induce IL-10 production by peripheral blood monocytes of healthy donors. The results show that Tat causes the production of IL-10 in a dose- and stimulation time-dependent manner. Investigations of the mechanisms involved in signal transduction show that (i) the calcium pathway is not or only slightly involved in Tat-induced IL-10 production, (ii) the protein kinase C pathway plays an essential role, and (iii) monocyte stimulation by Tat results in the intranuclear translocation of transcription factor NF-kappaB and in the induction of phosphorylation of the mitogen-activated protein kinases ERK1 and ERK2; activation of these two potential substrates of protein kinase C is required for the production of IL-10. Finally, our results suggest that the effect of Tat is exerted at the membrane level and that the active domain is located within N-terminal residues 1 to 45. This production of IL-10 induced by Tat could participate in the progression of HIV infection to AIDS.
Badou
A
A
Laboratoire d'Immuno-Virologie EA3038, Université Paul Sabatier, 31062 Toulouse Cedex, France.
Bennasser
Y
Y
Moreau
M
M
Leclerc
C
C
Benkirane
M
M
Bahraoui
E
E
D002118:Calcium / Q000378:metabolism; D015696:Gene Products, tat / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D016328:NF-kappa B; D054322:tat Gene Products, Human Immunodeficiency Virus; D016753:Interleukin-10; D011493:Protein Kinase C; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium