Synergistic activation of nuclear factor kappaB (NF-kappaB)by bacterial chemoattractant and tumor necrosis factor alpha (TNFalpha) is mediated by p38MAPK-dependent RelA acetylation

Abstract In the host immune system, leukocytes are often exposed to multiple inflammation inducers. NF-kB is of considerable importance in leukocyte function owing to its ability to activate the transcription of many proinflammatory immediate-early genes. Tremendous efforts have been made toward understanding how NF-kB is activated by various inducers. However, most research on NF-kB regulation has been focused on understanding how NF-kB is activated by a single inducer. This is unlike the situation in human immune system where multiple inflammation inducers, including both exogenous and endogenous mediators, are present concurrently. We now present evidence that fMLP, a bacterial chemoattractant, synergizes with TNFa to induce NF-kB activation and the resultant inflammatory response in vitro and in vivo. The mechanism of synergistic activation of NF-kB by bacterial fMLP and TNFa may involve in induction of RelA acetylation, which is regulated by p38 MAP kinase. Thus, the present studies provide direct evidence for the synergistic induction of NF-kB-dependent inflammatory responses by both exogenous and endogenous inducers. The ability of fMLP to synergize with TNFa and activate NF-kB represents a novel and potentially important mechanism through which bacterial fMLP can not only attracts leukocytes but also directly contribute to inflammation by synergizing with endogenous mediator TNFa.