Role of TLR-4 in liver macrophage and endothelial cell responsiveness during acute endotoxemia

Li C. Chen, Ronald E. Gordon, Jeffrey D. Laskin, Debra L. Laskin

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


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-κB 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.

Original languageEnglish
Pages (from-to)311-326
Number of pages16
JournalExperimental and Molecular Pathology
Issue number3
StatePublished - Dec 2007


  • Eicosanoids
  • Inflammatory mediators
  • Leukotrienes
  • MAP kinases
  • Prostaglandins


Dive into the research topics of 'Role of TLR-4 in liver macrophage and endothelial cell responsiveness during acute endotoxemia'. Together they form a unique fingerprint.

Cite this