LIVER X RECEPTOR AGONIST GW3965 DOSE-DEPENDENTLY REGULATES LPS-MEDIATED LIVER INJURY AND MODULATES POSTTRANSCRIPTIONAL TNF-α PRODUCTION AND P38 MITOGEN-ACTIVATED PROTEIN KINASE ACTIVATION IN LIVER MACROPHAGES

Abstract

Modulation of the host inflammatory response to infection may be a key approach to improve the outcome of patients with sepsis and organ injury. We previously reported that pretreatment of rats with the liver X receptor (LXR) agonist GW3965 reduced the liver injury associated with endotoxemia and attenuated the production of TNF-alpha by rat Kupffer cells. Here, we examine the dose-dependent effect of GW3965 on liver injury and cytokine production in a rat model of endotoxemia and explore the mechanisms underlying TNF-alpha attenuation in Kupffer cells. Low doses of GW3965 (0.1 or 0.3 mg/kg) administered 30 min before infusion of LPS and peptidoglycan significantly attenuated the increase in plasma levels of the liver injury markers alanine aminotransferase and bilirubin (6 h) as well as the inflammatory mediators TNF-alpha (1 h) and prostaglandin E2 (6 h) associated with endotoxemia. In contrast, pretreatment with a higher dose of GW3965 (1.0 mg/kg) had no such effect. Studies in primary cultures of rat Kupffer cells demonstrated that LXR agonist treatment attenuated both the secreted and cell-associated levels of TNF-alpha, whereas TNF-alpha mRNA levels were not altered. Phosphorylated p38 mitogen-activated protein kinase, which plays a major role in production of TNF-alpha at the posttranscriptional level, was attenuated by GW3965 treatment in Kupffer cells. Experiments in murine LXR-deficient Kupffer cells demonstrated enhanced production of TNF-alpha in Kupffer cells from LXR-alpha(-/-) mice when challenged with LPS compared with LXR-beta(-/-) and wild-type Kupffer cells. Taken together, these results argue in favor of a novel mechanism for LXR-mediated attenuation of liver injury by interfering with posttranscriptional regulation of TNF-alpha in Kupffer cells.

Liver X Receptor Protects against Liver Injury in Sepsis Caused by Rodent Cecal Ligation and Puncture

“…We and others have reported that LXR protects against lipopolysaccharide (LPS)-induced tissue injury, demonstrating protective effects on the liver and the lung [22,30]. Against this background, we hypothesized that LXR could be a node in the complex regulation of the pathogenesis of polymicrobial sepsis.…”

“…This may be attributable to differences in the models and how the agonist was given. In the endotoxemia model [22,23], agonist and LPS were given intravenously, and monocytes and liver Kupffer cells were exposed rapidly. Plasma TNF-a release is an early event with a relatively short time-frame in this model.…”

“…We previously reported that administration of the synthetic LXR agonist GW3965 reduced the liver injury and dysfunction in experimental endotoxemia by suppressing the inflammatory response in Kupffer cells [22,23]. The aim of the present study was to elucidate whether LXR plays a role in the pathophysiology of experimental sepsis, using rodent models of polymicrobial sepsis caused by cecal ligation and puncture (CLP).…”

Activation of liver X receptors promotes inflammatory cytokine mRNA degradation by upregulation of tristetraprolin

“…We have previously reported that ABCA1 is important for apolipoprotein A-I/TTP pathway-mediated post-transcriptional control of inflammatory cytokine mRNA decay [23]. Additionally, there is an abundance of evidence indicating that LXR agonist inhibits MAPK superfamily activation both in vitro and in vivo [24,25]. In the light of these data, we hypothesized that LXR activation could promote TTP expression and TTP-mediated inflammatory cytokine mRNA decay.…”

“…In some cell types, LXR activation inhibits ERK1/2 and p38 MAPK signaling pathways [24,25]. To verify whether LXR activation also inhibits these two signaling pathways in LPS-stimulated THP-1 macrophages, western blot analysis was carried out for phosho-ERK1/2 and phosho-p38 MAPK.…”