Mycobacteria-induced TNF-alpha and IL-10 formation by human macrophages isdifferentially regulated at the level of mitogen-activated protein kinase activity

The clinical course of mycobacterial infections is linked to the capacity o f pathogenic strains to modulate the initial antimycobacterial response of the macrophage. To elucidate some of the mechanisms involved, we studied ea rly signal transduction events leading to cytokine formation by human monoc yte-derived macrophages (MDM) in response to clinical isolates of Mycobacte rium avium. TNF-alpha production induced by M. avium was inhibited by anti- CD14 mAbs, but not by Abs against the macrophage mannose receptor. Analysis of mitogen-activated protein (MAP) kinase activation (extracellular signal -regulated kinase 1/2, p38, and c-Jun NH2-terminal kinase) showed a rapid p hosphorylation of all three subfamilies in response to M. avium, which was inhibited by anti-CD14 Abs. Using highly specific inhibitors of p38 (SB2035 80) and MAP kinase kinase-1 (PD98059), we found that activation of the extr acellular signal-regulated kinase pathway, but not of p38, was essential fo r the M. avium-induced TNF-alpha formation. In contrast, IL-10 production w as abrogated by the p38 inhibitor, but not by the MAP kinase kinase-1 inhib itor. In conclusion, M. avium-induced secretion of TNF-alpha and IL-10 by h uman macrophages is differentially regulated at the level of MAP kinase act ivity.