Brand Stephan, Dambacher Julia, Beigel Florian, Zitzmann Kathrin, Heeg Malte H J, Weiss Thomas S, Prüfer Thomas, Olszak Torsten, Steib Christian J, Storr Martin, Göke Burkhard, Diepolder Helmut, Bilzer Manfred, Thasler Wolfgang E, Auernhammer Christoph J
Department of Medicine II, University-Hospital Munich-Grosshadern and University of Munich, Marchioninistrasse 15, 81377 Munich, Germany.
Am J Physiol Gastrointest Liver Physiol. 2007 Apr;292(4):G1019-28. doi: 10.1152/ajpgi.00239.2006. Epub 2007 Jan 4.
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.
白细胞介素10样细胞因子白细胞介素22由活化的T细胞产生。在本研究中，我们分析了该细胞因子系统在肝细胞中的作用。通过逆转录聚合酶链反应（RT-PCR）和定量PCR进行表达研究。通过蛋白质免疫印迹实验和酶联免疫吸附测定（ELISA）分析信号转导。通过MTS和[³H]胸苷掺入试验测量细胞增殖。在体外恢复试验中研究肝细胞再生。白细胞介素22与其在人肝细胞和原代人肝细胞上表达的受体复合物结合导致丝裂原活化蛋白激酶（MAPKs）、蛋白激酶B（Akt）和信号转导子和转录激活子（STAT）蛋白的激活。白细胞介素22刺激细胞增殖和迁移，磷脂酰肌醇3激酶抑制剂渥曼青霉素均显著抑制二者。白细胞介素22增加细胞因子信号转导抑制因子（SOCS）-3以及促炎细胞因子白细胞介素6、白细胞介素8和肿瘤坏死因子-α（TNF-α）的mRNA表达。SOCS-1/3过表达消除白细胞介素22诱导的STAT激活并降低白细胞介素22介导的肝细胞再生。在不同形式的人类肝炎中可检测到肝脏白细胞介素22 mRNA表达，在巨细胞病毒感染后的体内小鼠T细胞介导的肝炎中肝脏白细胞介素22 mRNA水平升高，而在缺血再灌注损伤的体内模型中未观察到显著差异。总之，白细胞介素22通过激活Akt和STAT信号通路增加肝细胞增殖和肝细胞迁移，从而促进肝细胞再生，而SOCS-1/3过表达可消除这一作用。
