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: Stephan Brand, Julia Dambacher, Florian Beigel, Kathrin Zitzmann, Malte H J Heeg, Thomas S Weiss, Thomas Prüfer, Torsten Olszak, Christian J Steib, Martin Storr, Burkhard Göke, Helmut Diepolder, Manfred Bilzer, Wolfgang E Thasler, Christoph J Auernhammer
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 292 Issue 4 Pg. G1019-28 (Apr 2007) ISSN: 0193-1857 [Print] United States
• PMID: 17204547 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammation Mediators
• Interleukins
• RNA, Messenger
• Receptors, Interleukin
• SOCS1 protein, human
• SOCS3 protein, human
• STAT Transcription Factors
• Suppressor of Cytokine Signaling 1 Protein
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins
• interleukin-22 receptor
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Cell Culture Techniques
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Hepatectomy
• Hepatitis (metabolism)
• Hepatocytes (drug effects, metabolism)
• Humans
• Inflammation Mediators (metabolism)
• Interleukins (metabolism, pharmacology)
• Liver (cytology, metabolism, surgery)
• Liver Regeneration
• Lymphocyte Activation
• Mice
• Mice, Inbred C57BL
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Messenger (metabolism)
• Receptors, Interleukin (genetics, metabolism)
• STAT Transcription Factors (metabolism)
• Signal Transduction (drug effects)
• Suppressor of Cytokine Signaling 1 Protein
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins (genetics, metabolism)
• T-Lymphocytes (metabolism)
• Time Factors
• Transfection
• Up-Regulation
• Interleukin-22