Synergistic Activation of NF-κB by Bacterial Chemoattractant and TNFα Is Mediated by p38 MAPK-dependent RelA Acetylation

In the host immune system, leukocytes are often exposed to multiple inflammation inducers. NF-kappa B is of considerable importance in leukocyte function because of its ability to activate the transcription of many proinflammatory immediate-early genes. Tremendous efforts have been made toward understanding how NF-kappa B is activated by various inducers. However, most research on NF-kappa B regulation has been focused on understanding how NF-kappa B is activated by a single inducer. This is unlike the situation in the human immune system where multiple inflammation inducers, including both exogenous and endogenous mediators, are present concurrently. We now present evidence that the formylated peptide f-Met-Leu-Phe (fMLP), a bacterial chemoattractant, synergizes with TNF alpha to induce NF-kappa B activation and the resultant inflammatory response in vitro and in vivo. The mechanism of synergistic activation of NF-kappa B by bacterial fMLP and TNF alpha may be involved in the induction of RelA acetylation, which is regulated by p38 MAPK. Thus, this study provides direct evidence for the synergistic induction of NF-kappa B-dependent inflammatory responses by both exogenous and endogenous inducers. The ability of fMLP to synergize with TNF alpha and activate NF-kappa B represents a novel and potentially important mechanism through which bacterial fMLP not only attracts leukocytes but also directly contributes to inflammation by synergizing with the endogenous mediator TNF alpha.