title: Mesenchymal stem cells and Interleukin-6 attenuate liver fibrosis in mice.
abstract: BACKGROUND
  Mesenchymal stem cell (MSC) transplantation has emerged as a promising therapy for liver fibrosis. Issues concerning poor MSC survival and engraftment in the fibrotic liver still persist and warrant development of a strategy to increase MSC potency for liver repair. The present study was designed to examine a synergistic role for Interleukin-6 (IL-6) and MSCs therapy in the recovery of carbon tetrachloride (CCl(4)) induced injured hepatocytes in vitro and in vivo.
  
  
  METHODS
  Injury was induced through 3 mM and 5 mM CCl(4) treatment of cultured hepatocytes while fibrotic mouse model was established by injecting 0.5 ml/kg CCl(4) followed by treatment with IL-6 and MSCs. Effect of MSCs and IL-6 treatment on injured hepatocytes was determined by lactate dehydrogenase release, RT-PCR for (Bax, Bcl-xl, Caspase3, Cytokeratin 8, NFκB, TNF-α) and annexin V apoptotic detection. Analysis of MSC and IL-6 treatment on liver fibrosis was measured by histopathology, PAS, TUNEL and Sirius red staining, RT-PCR, and liver function tests for Bilirubin and Alkaline Phosphatase (ALP).
  
  
  RESULTS
  A significant reduction in LDH release and apoptosis was observed in hepatocytes treated with a combination of MSCs and IL-6 concomitant with upregulation of anti-apoptotic gene Bcl-xl expression and down regulation of bax, caspase3, NFκB and TNF-α. Adoptive transfer of MSCs in fibrotic liver pretreated with IL-6 resulted increased MSCs homing and reduced fibrosis and apoptosis. Hepatic functional assessment demonstrated reduced serum levels of Bilirubin and ALP.
  
  
  CONCLUSIONS
  Pretreatment of fibrotic liver with IL-6 improves hepatic microenvironment and primes it for MSC transplantation leading to enhanced reduction of liver injury after fibrosis. Synergistic effect of IL-6 and MSCs seems a favored therapeutic option in attenuation of liver apoptosis and fibrosis accompanied by improved liver function.
authors.affiliation: National Center of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Lahore, Pakistan.
authors.forename: Ghazanfar Ali
authors.initials: GA
authors.lastname: Nasir
authors.forename: Sadia
authors.initials: S
authors.lastname: Mohsin
authors.forename: Mohsin
authors.initials: M
authors.lastname: Khan
authors.forename: Sulaiman
authors.initials: S
authors.lastname: Shams
authors.forename: Gibran
authors.initials: G
authors.lastname: Ali
authors.forename: Shaheen N
authors.initials: SN
authors.lastname: Khan
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
mesh_terms: D000818:Animals; D017209:Apoptosis; D002251:Carbon Tetrachloride / Q000494:pharmacology; D018920:Coculture Techniques; D005260:Female; D005786:Gene Expression Regulation; D006003:Glycogen / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D015850:Interleukin-6; D006003:Glycogen; D002251:Carbon Tetrachloride