HIV-1 Tat protein induces TNF-α and IL-10 production by human macrophages: Differential implication of PKC-βII and -δ 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-α 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-α production. Among the eight PKC isoforms present in macrophages, we show that only PKC-βΙΙ and -δ 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-κB. Using chemical inhibitors we show that (i) both ERK1/2 MAP kinase and NF-κB transcription factor play an important role in IL-10 and TNF-α production, in macrophages stimulated by Tat. However, p38 MAP kinase seems to be involved only in IL-10 and not TNF-α production.