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-l)-infected patients are primarily due to the capacity of the virus a nd its components to inactivate the immune system. HIV-1 Tat protein could participate in this immune system disorder. This protein is secreted by inf ected cells of HIV-infected patients and is free in the plasma, where it ca n interact and be taken up by both infected and noninfected cells. In asymp tomatic 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 sh ow that Tat causes the production of IL-10 in a dose- and stimulation time- dependent manner. Investigations of the mechanisms involved in signal trans duction 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 intra nuclear translocation of transcription factor NF-KB and in the induction of phosphorylation of the mitogen-activated protein kinases ERK1 and ERK2; ac tivation of these two potential substrates of protein kinase C is required for the production of IL-10. Finally, our results suggest that the effect o f Tat is exerted at the membrane level and that the active domain is locate d within N-terminal residues 1 to 45. This production of IL-10 induced by T at could participate in the progression of HIV infection to AIDS.