title: Acute pancreatitis induces FasL gene expression and apoptosis in the liver.
abstract: BACKGROUND
  Liver injury is an important prognostic indicator in acute pancreatitis. We previously demonstrated that Kupffer cell-derived cytokines mediate liver injury. In this work, we sought to characterize the role of Fas Ligand (FasL) in liver injury during acute pancreatitis.
  
  
  METHODS
  Acute pancreatitis was induced in mice using cerulein; serum FasL, AST, ALT, liver FasL, p38-MAPK, and caspase-3 were measured. FasL mRNA and protein and its receptor (Fas) were determined in rat Kupffer cells treated with elastase (1 U/ml) to mimic acute pancreatitis. Apoptosis was measured by flow cytometry.
  
  
  RESULTS
  Cerulein-induced pancreatitis increased serum AST, ALT, and FasL and up-regulated liver FasL (1315 +/- 111 versus 310 +/- 164 pg/ml, P = 0.002 versus sham), while inducing p38-MAPK phosphorylation (P < 0.01 versus sham) and cleavage of caspase-3 (P < 0.04 versus sham); all were attenuated by pretreatment with the Kupffer cell inhibitor, gadolinium (all P < 0.003). In vitro, elastase induced a time-dependent increase in Kupffer cell FasL protein (FasL = 404 +/- 94 versus 170 +/- 40, P = 0.02, versus control), a 100-fold increase in FasL mRNA, and up-regulated Fas (FasL receptor). Gadolinium significantly attenuated the elastase-induced increase in FasL and FasL mRNA (FasL = 230 +/- 20 versus 404 +/- 94, P = 0.01, versus elastase) but had little effect on Fas. Additionally, elastase-primed Kupffer cell media induced apoptosis in hepatocytes (29 +/- 1 versus 16% +/- 1%; versus control, P < 0.001).
  
  
  CONCLUSIONS
  Acute pancreatitis induces liver injury and hepatocyte death while up-regulating FasL, p38-MAPK, and caspase-3. Fas is up-regulated within Kupffer cells, suggesting that FasL may autoregulate its production by inducing its originator-cell death. The ability to manipulate interactions between Kupffer cells and hepatocytes may have important therapeutic implications.
authors.affiliation: Department of Surgery, James A. Haley Veterans Affairs Medical Center, University of South Florida Health Sciences Center, Tampa, Florida, USA.
authors.forename: Scott F
authors.initials: SF
authors.lastname: Gallagher
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Kathryn
authors.initials: K
authors.lastname: Baksh
authors.forename: Krista
authors.initials: K
authors.lastname: Haines
authors.forename: Heather
authors.initials: H
authors.lastname: Carpenter
authors.forename: P K
authors.initials: PK
authors.lastname: Epling-Burnette
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Peng
authors.forename: James
authors.initials: J
authors.lastname: Norman
authors.forename: Michel M
authors.initials: MM
authors.lastname: Murr
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D015870:Gene Expression; D022781:Hepatocytes; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010195:Pancreatitis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015854:Up-Regulation; D019014:fas Receptor; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; C491899:Fas protein, mouse; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; D048051:p38 Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases