LPS plays a major role in the pathogenesis of gram-negative sepsis (septic shock). LPS is a very potent stimulator of the cells of the immune system. including macrophages, B cells and endothelial cells. Although generally beneficial, the host response to LPS can be detrimental and even life threatening when it is sustained systemically during bacterial sepsis. We found that soluble CD14 is required for LPS- mediated EC responses. We have recently observed that LPS rapidly induces the tyrosine phosphorylation of several ED proteins. Tyrosine phosphorylation has recently emerged as an important receptor signaling mechanism, therefore, the objectives of this revised application is to define the biochemical mechanisms by which LPS induces EC responses, specifically to define LPS-induced signaling events which lead to induction of IL-6 production. We propose to further elucidate these pathways in order to understand better the processes that mediate the EC responses to LPS.
