HIV-1 Tat protein induces IL-10 production by an alternative TNF-α-independent pathway in monocytes: Role of PKC-δ and p38 MAP kinase

HIV-1 Tat protein stimulates the production of both TNF-α and IL-10 in human monocytes. Taking into account the ability of TNF-α to induce IL-10 production, we evaluated the link between Tat, TNF-α 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-α antibodies, IL-10 production is only partially inhibited; (ii) in a calcium-free medium, while TNF-α production is totally inhibited, Tat continues to induce IL-10; (iii) under these conditions, Tat-mediated IL-10 production is associated with PKC-δ activation; and (iv) downstream of PKC, p38 MAP kinase is crucial for TNF-α 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-α production. In consequence, HIV-1 may escape immune surveillance and thus promote the establishment of an immunosuppressive state.