title: Role of TLR-4 in liver macrophage and endothelial cell responsiveness during acute endotoxemia.
abstract: Liver macrophages and endothelial cells have been implicated in hepatotoxicity induced by endotoxin (ETX). In these studies, we analyzed the role of toll-like receptor 4 (TLR-4) in the response of these cells to acute endotoxemia. Treatment of control C3H/HeOuJ mice with ETX (3 mg/kg, i.p.) resulted in increased numbers of activated macrophages in the liver. This was associated with morphological changes in the cells and a rapid (within 3 h) induction of nitric oxide synthase-2, cyclooxygenase-2, microsomal PGE synthase-1, interleukin-1 beta and tumor necrosis factor alpha gene expression. In endothelial cells, acute endotoxemia led to increased expression of these genes, as well as 5-lipoxygenase. In contrast, liver sinusoidal cells from C3H/HeJ TLR-4 mutant mice were relatively unresponsive to ETX. Treatment of C3H/HeOuJ, but not C3H/HeJ mice with ETX, resulted in activation of transcription factors AP-1 and NF-kappaB in liver sinusoidal cells, which was evident within 3 h. Whereas in macrophages, transcription factor activation was transient, in endothelial cells, it persisted for 24 h. In C3H/HeOuJ mice treated with ETX, activation of p38 MAP kinase was also evident in macrophages and endothelial cells, and JNK kinase in macrophages. In contrast, reduced protein kinase B (AKT) was noted in macrophages. In C3H/HeJ mice, ETX administration also led to activation of p38 MAP kinase in macrophages with no effects on JNK, p44/42 MAP kinase or AKT. These studies demonstrate that liver macrophages and endothelial cells are highly responsive to acute endotoxemia. Moreover, this activity is largely dependent on TLR-4.
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Li C
authors.initials: LC
authors.lastname: Chen
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Gordon
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Laskin
authors.forename: Debra L
authors.initials: DL
authors.lastname: Laskin
mesh_terms: D000818:Animals; D015777:Eicosanoids / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D019446:Endotoxemia / Q000378:metabolism*; D004731:Endotoxins / Q000494:pharmacology; D005786:Gene Expression Regulation; D008099:Liver / Q000166:cytology* / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D015777:Eicosanoids; D004731:Endotoxins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4