title: The peptidyl-prolyl isomerase, Pin1, facilitates NF-kappaB binding in hepatocytes and protects against hepatic ischemia/reperfusion injury.
abstract: OBJECTIVE
  Our previous work suggested an important role for the peptidyl-prolyl isomerase, Pin1, in hepatic NF-kappaB activation and liver injury during ischemia/reperfusion (I/R). In this study, we sought to determine the function of Pin1 in the injury response to hepatic I/R.
  
  
  METHODS
  Wild-type and Pin1(-/-) mice were subjected to partial hepatic I/R. In addition, hepatocytes and Kupffer cells were isolated from these mice.
  
  
  RESULTS
  Pin1(-/-) mice had reduced hepatic NF-kappaB activation and more liver injury after I/R than wild-type mice. The increased injury was not a result of enhanced inflammation as Pin1(-/-) mice had the same level of proinflammatory cytokine production and less neutrophil accumulation in the liver. The reduced NF-kappaB activation was not a result of a defect in nuclear translocation of NF-kappaB. In fact, hepatic nuclear p65 protein expression was higher in Pin1(-/-) mice than wild-type mice. This suggests that Pin1 is important for NF-kappaB-DNA binding. This effect was specific to hepatocytes as isolated Kupffer cells from wild-type and Pin1(-/-) mice were identical in their activation of NF-kappaB and production of cytokines after stimulation. In contrast, hepatocytes stimulated with TNFalpha had greatly reduced NF-kappaB activation, reduced production of the CXC chemokine, MIP-2, and increased cell death.
  
  
  CONCLUSIONS
  These data suggest that Pin1 is a critical regulator of NF-kappaB activation in hepatocytes and its role in these cells appears to confer direct protective effects.
authors.affiliation: The Laboratory of Trauma, Sepsis & Inflammation Research, Department of Surgery, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0558, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuboki
authors.forename: Nozomu
authors.initials: N
authors.lastname: Sakai
authors.forename: Callisia
authors.initials: C
authors.lastname: Clarke
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schuster
authors.forename: John
authors.initials: J
authors.lastname: Blanchard
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Edwards
authors.forename: Alex B
authors.initials: AB
authors.lastname: Lentsch
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020672:I-kappa B Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000201:enzymology* / Q000293:injuries*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000494:pharmacology
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C000606205:Nfkbia protein, mouse; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse