Mycobacterium aviumComplex Activates Nuclear Factor κB via Induction of Inflammatory Cytokines

A variety of microorganisms has been reported to directly induce NF-κB, a critical step in the regulation of genes involved in the cellular immune response. In this study, we demonstrate that proinflammatory cytokines such as tumor necrosis factor α (TNFα) produced upon activation by theMycobacterium aviumcomplex (MAC) preceed NF-κB activity in U937, a human monocytoid cell line. MAC induction of TNFα mRNA expression was detected within 15 min after MAC infection, whereas enhanced NF-κB binding activity was not detected until 90 to 120 min postinfection. Supershift analysis revealed increased p50 in the MAC-induced NF-κB binding complexes. Consistent with an autocrine mechanism, anti-TNFα antibody and dexamethasone, a known cytokine inhibitor, both completely suppressed the effect of MAC on the induction of NF-κB. Taken together, these findings suggest that exposure of monocyte cell membranes to MAC induces endogenous TNFα, which in turn enhances NF-κB binding activity. The rapid induction of TNFα may be important in the initial host response to MAC infection.