Synergistic activation of NF-{kappa}B by bacterial chemoattractant and TNF{alpha} is mediated by p38 MAPK-dependent RelA acetylation.

In the host immune system, leukocytes are often exposed to multiple inflammation inducers. NF-κB 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-κB is activated by various inducers. However, most research on NF-κB regulation has been focused on understanding how NF-κB 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 TNFα to induce NF-κB activation and the resultant inflammatory response in vitro and in vivo. The mechanism of synergistic activation of NF-κB by bacterial fMLP and TNFα 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-κB-dependent inflammatory responses by both exogenous and endogenous inducers. The ability of fMLP to synergize with TNFα and activate NF-κB 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 TNFα.

Synergistic induction of inflammation by bacterial products lipopolysaccharide and fMLP: an important microbial pathogenic mechanism.

A wide variety of stimuli have been shown to induce inflammation, but bacteria products/components are considered the major inducers during bacterial infections. We previously demonstrated that bacterial products/components such as LPS, a glycolipid component of the bacterial outer membrane, and formylated peptides (fMLP), a bacterial-derived peptide, induced proinflammatory cytokine gene expression in human peripheral blood monocytes. We now present evidence that mixtures of bacterial products/components LPS and fMLP behave synergistically in the induction of inflammation in vitro and in vivo. Furthermore, our results indicate that the TLR4 and the IKKbeta-IkappaBalpha signaling pathways are involved in the synergistic induction of inflammatory cytokines. The mechanism of synergistic activation of NF-kappaB is depended on nuclear translocation of p65 and phosphorylation of p65 at both Ser536 and Ser276 sites. These results demonstrate an important role for bacterial products/components from lysed bacteria in the pathogenesis of infectious diseases. We believe that this synergistic induction of inflammation by bacterial products LPS and fMLP represents an important pathogenic mechanism during bacterial infection, which may suggest novel therapeutic strategies or targets to minimize host injury following bacterial infection.