An important mechanism of innate immunity is the inflammatory response. However, exaggerated inflammatory responses to endotoxin may cause septic shOCk. In the United States, about 400,000 patients per annum develop septic shock and about 30% of these patients die. Recent genetic evidence suggests that Tpl2 (tumor progression locus-2) plays a central role in endotoxin-mediated macrophage activation. Despite the central role of Tpl2 in macrophage activation, little is known about how this LPS-responsive kinase is regulated. In p105 null macrophages, Tpl2 is barely detectable due to its rapid degradation, which is associated with a severe defect in LPS-stimulated MEKJERK activation and downstream signaling events. These findings suggest that the NF-kB1/Tpl2 interaction plays a critical role in mediating the signal transductions leading to macrophage activation. The goal of this proposal is to understand the biochemical mechanism mediating the NF-kB1/Tpl2 interaction and the in vivo role of this molecular interplay in regulating macrophage function.
The aims presented are: (1) to map the domains of NF-kB1 that are required for Tpl2 regulation and (2) to investigate the in vivo role of NF-kB1/rpl2 interactions in macrophage activation and innate immune responses using transgenic mouse models.
