title: Liver X receptor agonist GW3965 dose-dependently regulates lps-mediated liver injury and modulates posttranscriptional TNF-alpha 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.
authors.affiliation: Institute for Surgical Research, Rikshospitalet and University of Oslo, Oslo, Norway.
authors.forename: Yun Yong
authors.initials: YY
authors.lastname: Wang
authors.forename: Maria K
authors.initials: MK
authors.lastname: Dahle
authors.forename: Knut R
authors.initials: KR
authors.lastname: Steffensen
authors.forename: Finn P
authors.initials: FP
authors.lastname: Reinholt
authors.forename: Jon L
authors.initials: JL
authors.lastname: Collins
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
authors.forename: Ansgar O
authors.initials: AO
authors.lastname: Aasen
authors.forename: Jan-Ake
authors.initials: JA
authors.lastname: Gustafsson
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Wang
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D001663:Bilirubin / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D007728:Kupffer Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D000071518:Liver X Receptors; D008297:Male; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D010457:Peptidoglycan / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D010457:Peptidoglycan; D014409:Tumor Necrosis Factor-alpha; D000410:Alanine Transaminase; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone; D001663:Bilirubin