title: Smad3 signaling in the regenerating liver: implications for the regulation of IL-6 expression.
abstract: Liver regeneration is vital for graft survival and adequate organ function. Smad activation regulates hepatocyte proliferation and macrophage function. The aim of the current study was to evaluate the impact of Smad3 signaling during liver regeneration in the mouse. Male C57Bl/6 wild-type (wt) mice or mice deficient in Smad3 (Smad3(-/-) ) were subjected to a 70% partial hepatectomy (pHx) or sham surgery and sacrificed 24, 42, or 48 h later. Tissue was analyzed for TGF-β signaling, the mitogenic cytokine response [i.e., tumor necrosis factor alpha, TNF-α; interleukin (IL)-6], and liver regeneration. Partial hepatectomy stimulated a strong regenerative response measured by proliferating cell nuclear antigen-positive hepatocytes 42 and 48 h post-pHx in conjunction with an increased expression of IL-6, TNF-α, and Smad2/3 phosphorylation 24 h post-pHx in both hepatocytes and nonparenchymal cells. Surprisingly, Smad3 deficiency led to reduced hepatocyte proliferation 42 h post-pHx which recovered by 48 h, a process that correlated with and was preceded by significant reductions in IL-6 expression and signal transducer and activator of transcription 3 phosphorylation, and cyclin D1 induction 24 h post-pHx. Loss of Smad3 signaling suppresses the expression of key mitogenic cytokines and delays hepatocellular regeneration. Therapies directed at finely regulating Smad3 activation early within the regenerating liver may prove useful in promoting liver cell proliferation and restoration of liver mass.
authors.affiliation: Department of General Surgery, University of Ulm, Ulm, Germany; Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kremer
authors.forename: Gakuhei
authors.initials: G
authors.lastname: Son
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.forename: Sherri M
authors.initials: SM
authors.lastname: Moore
authors.forename: Amber
authors.initials: A
authors.lastname: Norris
authors.forename: Giulia
authors.initials: G
authors.lastname: Manzini
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wheeler
authors.forename: Ian N
authors.initials: IN
authors.lastname: Hines
mesh_terms: D000818:Animals; D006498:Hepatectomy; D015850:Interleukin-6 / Q000096:biosynthesis*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D050828:Protein Inhibitors of Activated STAT / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000502:physiology*
chemical_list: D015850:Interleukin-6; C109279:Pias3 protein, mouse; D050828:Protein Inhibitors of Activated STAT; D050796:STAT3 Transcription Factor; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C494087:Stat3 protein, mouse
keywords: Smad family; Stat3; cytokines; liver regeneration; liver signaling; partial hepatectomy