Regulation of TLR4-mediated signaling by IBP/Def6, a novel activator of Rho GTPases.
TLRs play a fundamental role in innate immune responses. Although Rho GTPases have been implicated in TLR-mediated signaling pathways, the molecules that control their activation in response to TLR engagement are largely unknown. IFN regulatory factor-4-binding protein (IBP; which is encoded by the gene Def6) is a unique type of activator for Rac that plays a crucial role in TCR-mediated signaling and adaptive immune responses. Here, we demonstrate that IBP/Def6 also controls innate immune responses by modulating TLR-induced signaling events. Mice deficient in IBP/Def6 are protected from LPS-induced septic shock. This protection is associated with a decrease in the production of proinflammatory cytokines and is accompanied by diminished activation of MAPKs and NF-kappaB. Our results thus identify IBP/Def6 as a novel component of the TLR4-induced signaling cascade that controls the production of proinflammatory cytokines.
Chen
Qinzhong
Q
Columbia University, 630 West 168th Street, New York, NY 10032, USA.
Gupta
Sanjay
S
Pernis
Alessandra B
AB
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000276:immunology / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors; D007113:Immunity, Innate; D018836:Inflammation Mediators; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D016207:Cytokines; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D009687:Nuclear Proteins; D051197:Toll-Like Receptor 4; D020741:rho GTP-Binding Proteins; C473249:Def6 protein, mouse; C493487:Tlr4 protein, mouse