title: Dexamethasone attenuates lipopolysaccharide-induced liver injury by downregulating glucocorticoid-induced tumor necrosis factor receptor ligand in Kupffer cells.
abstract: OBJECTIVE
  Glucocorticoid-induced tumor necrosis factor receptor ligand (GITRL) plays pro-inflammatory roles in immune response. Thus, our aim was to assess if dexamethasone attenuates lipopolysaccharide (LPS)-induced liver injury by affecting GITRL in Kupffer cells (KC).
  
  
  METHODS
  A BALB/c mouse model of liver injury was established by i.p. injecting with LPS (10 mg/kg) co-treated with or without dexamethasone (3 mg/kg). Blood and liver samples were obtained for analysis of liver morphology, GITRL expression, hepatocellular function and cytokine levels at 24 h after injection. KC were isolated and challenged by LPS (1 µg/mL), with or without dexamethasone (10 µM) co-treatment, or with GITRL siRNA pre-transfection. The GITRL expression and cytokine levels were assayed at 24 h after challenge.
  
  
  RESULTS
  Dexamethasone treatment significantly improved the survival rate of endotoxemic mice (P < 0.05), whereas serum alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor (TNF)-α, interleukin (IL)-6 and γ-interferon levels were significantly decreased (P < 0.05, respectively). Concurrently, LPS-induced hepatic tissue injury was attenuated as indicated by morphological analysis; and expression of GITRL in liver tissue and KC was downregulated (P < 0.05). Consistent with these in vivo experiments, inhibited expression of GITRL, TNF-α and IL-6 caused by dexamethasone treatment were also observed in LPS-stimulated KC. The GITRL, TNF-α and IL-6 expression was also significantly inhibited by GITRL gene silencing.
  
  
  CONCLUSIONS
  The TNF-α and IL-6 expression of LPS-stimulated KC was inhibited by GITRL gene silencing. Dexamethasone attenuates LPS-induced liver injury, at least proportionately, by downregulating GITRL in KC.
authors.affiliation: Key Laboratory of Chongqing Hepatobiliary Surgery             Key Laboratory of Molecular Biology for Infectious Diseases, People's Republic of China Ministry of Education, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.
authors.forename: Si D
authors.initials: SD
authors.lastname: Wei
authors.forename: Jin Z
authors.initials: JZ
authors.lastname: Li
authors.forename: Zuo J
authors.initials: ZJ
authors.lastname: Liu
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Jian P
authors.initials: JP
authors.lastname: Gong