title: Sphingosine kinase 1 dependent protein kinase C-δ activation plays an important role in acute liver failure in mice.
abstract: OBJECTIVE
  To investigate the role of protein kinase C (PKC)-δ activation in the pathogenesis of acute liver failure (ALF) in a well-characterized mouse model of D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced ALF.
  
  
  METHODS
  BALB/c mice were randomly assigned to five groups, and ALF was induced in mice by intraperitoneal injection of D-GaIN (600 mg/kg) and LPS (10 μg/kg). Kaplan-Meier method was used for survival analysis. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at different time points within one week were determined using a multiparameteric analyzer. Serum levels of high-mobility group box 1 (HMGB1), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 as well as nuclear factor (NF)-κB activity were determined by enzyme-linked immunosorbent assay. Hepatic morphological changes at 36 h after ALF induction were assessed by hematoxylin and eosin staining. Expression of PKC-δ in liver tissue and peripheral blood mononuclear cells (PBMCs) was analyzed by Western blot.
  
  
  RESULTS
  The expression and activation of PKC-δ were up-regulated in liver tissue and PBMCs of mice with D-GalN/LPS-induced ALF. Inhibition of PKC-δ activation with rottlerin significantly increased the survival rates and decreased serum ALT/AST levels at 6, 12 and 24 h compared with the control group (P < 0.001). Rottlerin treatment also significantly decreased serum levels of HMGB1 at 6, 12, and 24 h, TNF-α, IL-6 and IL-1 β at 12 h compared with the control group (P < 0.01). The inflammatory cell infiltration and necrosis in liver tissue were also decreased in the rottlerin treatment group. Furthermore, sphingosine kinase 1 (SphK1) dependent PKC-δ activation played an important role in promoting NF-κB activation and inflammatory cytokine production in ALF.
  
  
  CONCLUSIONS
  SphK1 dependent PKC-δ activation plays an important role in promoting NF-κB activation and inflammatory response in ALF, and inhibition of PKC-δ activation might be a potential therapeutic strategy for this disease.
authors.affiliation: Yan-Chang Lei, Department of Infectious Diseases, Zhejiang Hospital, Hangzhou 310013, Zhejiang Province, China.
authors.forename: Yan-Chang
authors.initials: YC
authors.lastname: Lei
authors.affiliation: Yan-Chang Lei, Department of Infectious Diseases, Zhejiang Hospital, Hangzhou 310013, Zhejiang Province, China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Yang
authors.affiliation: Yan-Chang Lei, Department of Infectious Diseases, Zhejiang Hospital, Hangzhou 310013, Zhejiang Province, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Yan-Chang Lei, Department of Infectious Diseases, Zhejiang Hospital, Hangzhou 310013, Zhejiang Province, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Luo
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005688:Galactosamine; D018836:Inflammation Mediators / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology*; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D017114:Liver Failure, Acute / Q000097:blood / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D008807:Mice, Inbred BALB C; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000097:blood / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D000099157:Sphingosine Kinase
chemical_list: D000410:Alanine Transaminase; D000893:Anti-Inflammatory Agents; D001219:Aspartate Aminotransferases; D015415:Biomarkers; D005688:Galactosamine; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D017853:Phosphotransferases (Alcohol Group Acceptor); D051745:Protein Kinase C-delta; D047428:Protein Kinase Inhibitors; D000099157:Sphingosine Kinase; C497259:Prkcd protein, mouse
keywords: Acute liver failure; Nuclear factor-κB; Protein kinase C-δ; Sphingosine kinase 1