The liver is a primary response organ in post-operative infections. Hepatocytes (HC), the primary cell type in the liver, take up and metabolize microbial products, respond directly to lipopolysaccharide (LPS), and release proteins into the circulation that regulate host-microbe interactions. In contrast to leukocytes and sepsis, relatively little is known about the anti-microbial responses of HC. We have previously shown that HC express both CDI4 and LBP, and that the expression of both of these proteins is increased in endotoxemic rats. More recently, we have shown that the endotoxemic liver expresses increased levels of TLR2, and that HC upregulate TLR2 in response to pro-inflammatory cytokines. In HC, functional TLR4 appears to be required both for stimulation with LPS, as well as for LPS-mediated desensitization. We suggest that LPS may desensitize HC by modulating signal transduction proteins common to TLR2, TLR4, and IL-IR1. We hypothesize that HC express microbial recognition proteins for three specialized purposes. First, HC possess the capacity to respond directly to microbial products, in a CD 14- and TLR-dependent manner to permit a rapid response to serious infections. However, these responses are downregulated by the microbial products themselves and/or by cytokines released subsequent to stimulation with these microbial products. Second, surface CDI4 and TLR on HC participate in the clearance of microbial products. Third, HC regulate the systemic response to infection through the release of soluble CD14. We will pursue these hypotheses in three interrelated Aims: 1) to determine the signaling function of microbial recognition systems in HC; 2) to determine the role of HC LPS recognition molecules in LPS clearance and the systemic response; and 3) to determine the mechanism of LPS-mediated desensitization of HC. We will take advantage of LBP, CDI4, TLR2, and TLR4 null mice, using both in vitro and in vivo systems to fully assess the roles of the LBP/CDI4/TLR pathway in the liver. Insights gained from these studies should significantly enhance our understanding of the earliest events in host-microbe interactions in surgical sepsis.
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