title: IL-22-mediated liver cell regeneration is abrogated by SOCS-1/3 overexpression in vitro.
abstract: The IL-10-like cytokine IL-22 is produced by activated T cells. In this study, we analyzed the role of this cytokine system in hepatic cells. Expression studies were performed by RT-PCR and quantitative PCR. Signal transduction was analyzed by Western blot experiments and ELISA. Cell proliferation was measured by MTS and [(3)H]thymidine incorporation assays. Hepatocyte regeneration was studied in in vitro restitution assays. Binding of IL-22 to its receptor complex expressed on human hepatic cells and primary human hepatocytes resulted in the activation of MAPKs, Akt, and STAT proteins. IL-22 stimulated cell proliferation and migration, which were both significantly inhibited by the phosphatidylinositol 3-kinase inhibitor wortmannin. IL-22 increased the mRNA expression of suppressor of cytokine signaling (SOCS)-3 and the proinflammatory cytokines IL-6, IL-8, and TNF-alpha. SOCS-1/3 overexpression abrogated IL-22-induced STAT activation and decreased IL-22-mediated liver cell regeneration. Hepatic IL-22 mRNA expression was detectable in different forms of human hepatitis, and hepatic IL-22 mRNA levels were increased in murine T cell-mediated hepatitis in vivo following cytomegalovirus infection, whereas no significant differences were seen in an in vivo model of ischemia-reperfusion injury. In conclusion, IL-22 promotes liver cell regeneration by increasing hepatic cell proliferation and hepatocyte migration through the activation of Akt and STAT signaling, which is abrogated by SOCS-1/3 overexpression.
authors.affiliation: Department of Medicine II, University-Hospital Munich-Grosshadern and University of Munich, Marchioninistrasse 15, 81377 Munich, Germany. stephan.brand@med.uni-muenchen.de
authors.forename: Stephan
authors.initials: S
authors.lastname: Brand
authors.forename: Julia
authors.initials: J
authors.lastname: Dambacher
authors.forename: Florian
authors.initials: F
authors.lastname: Beigel
authors.forename: Kathrin
authors.initials: K
authors.lastname: Zitzmann
authors.forename: Malte H J
authors.initials: MH
authors.lastname: Heeg
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Weiss
authors.forename: Thomas
authors.initials: T
authors.lastname: Prüfer
authors.forename: Torsten
authors.initials: T
authors.lastname: Olszak
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Steib
authors.forename: Martin
authors.initials: M
authors.lastname: Storr
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Helmut
authors.initials: H
authors.lastname: Diepolder
authors.forename: Manfred
authors.initials: M
authors.lastname: Bilzer
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Thasler
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Auernhammer
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006498:Hepatectomy; D006505:Hepatitis / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000601:surgery; D008115:Liver Regeneration; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D000097043:Interleukin-22
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D018836:Inflammation Mediators; D007378:Interleukins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D050791:STAT Transcription Factors; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000097043:Interleukin-22; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; C415369:interleukin-22 receptor