title: Interleukin-6 mediates angiotensinogen gene expression during liver regeneration.
abstract: BACKGROUND
  Angiotensinogen is the precursor of angiotensin II, which is associated with ischemia-reperfusion injury. Angiotensin II reduces liver regeneration after hepatectomy and causes dysfunction and failure of reduced-size liver transplants. However, the regulation of angiotensinogen during liver regeneration is still unclear.
  
  
  OBJECTIVE
  To investigate the regulation of angiotensinogen during liver regeneration for preventing angiotensin II-related ischemia-reperfusion injury during liver regeneration.
  
  
  METHODS
  A mouse in vitro partial hepatectomy animal model was used to evaluate the expression of interleukin-6 (IL-6) and angiotensinogen during liver regeneration. Serum IL-6 and angiotensinogen were detected by enzyme immunoassay (EIA). Angiotensinogen mRNA was detected by RT-PCR. Tissue levels of angiotensinogen protein were detected by Western blot analysis. Primary cultures of mouse hepatocytes were used to investigate IL-6-induced angiotensinogen. Chemical inhibitors were used to perturb signal transduction pathways. Synthetic double-stranded oligodeoxynucleotides (ODNs) were used as 'decoy' cis-elements to investigate transcription. Ki 67 staining and quantification were used to verify liver regeneration.
  
  
  RESULTS
  In the in vivo model, the levels of serum IL-6 and angiotensinogen correlated. In the in vitro model, IL-6 transcriptionally regulated angiotensinogen expression. Additionally, IL-6 mediated angiotensinogen expression through the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) and JAK/p38 signaling. Decoy ODN analyses revealed that STAT3 and nuclear factor-kB (NF-kB) also played critical roles in the transcriptional regulation of angiotensinogen by IL-6. IL-6-mediated signaling, JAK2, STAT3 and p38 inhibitors reduced angiotensinogen expression in the partially hepatectomized mice.
  
  
  CONCLUSIONS
  During liver regeneration, IL-6-enhanced angiotensinogen expression is dependent on the JAK/STAT3 and JAK/p38/NF-kB signaling pathways. Interruption of the molecular mechanisms of angiotensinogen regulation may be applied as the basis of therapeutic strategies for preventing angiotensin II-related ischemia-reperfusion injury during liver regeneration.
authors.affiliation: Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. hslai@ntu.edu.tw
authors.forename: Hong-Shiee
authors.initials: HS
authors.lastname: Lai
authors.forename: Wen-Hsi
authors.initials: WH
authors.lastname: Lin
authors.forename: Shuo-Lun
authors.initials: SL
authors.lastname: Lai
authors.forename: Hao-Yu
authors.initials: HY
authors.lastname: Lin
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Hsu
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Chou
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Lee
mesh_terms: D000808:Angiotensinogen / Q000097:blood / Q000235:genetics*; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D006498:Hepatectomy; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics* / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D000808:Angiotensinogen; D053612:Janus Kinases; D048051:p38 Mitogen-Activated Protein Kinases