Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, USA.
Gastroenterology. 2012 Jul;143(1):188-98.e7. doi: 10.1053/j.gastro.2012.03.044. Epub 2012 Apr 3.
BACKGROUND & AIMS: Proliferation of liver stem/progenitor cells (LPCs), which can differentiate into hepatocytes or biliary epithelial cells, is often observed in chronically inflamed regions of liver in patients. We investigated how inflammation might promote proliferation of LPCs.
We examined the role of interleukin (IL)-22, a survival factor for hepatocytes, on proliferation of LPCs in patients with chronic hepatitis B virus (HBV) infection and in mice. Proliferation of LPCs in mice was induced by feeding a diet that contained 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC).
Hepatic expression of IL-22 was increased in patients with HBV and correlated with the grade of inflammation and proliferation of LPCs. Mice on the DDC diet that overexpressed an IL-22 transgene specifically in liver (IL-22TG), or that were infected with an IL-22-expressing adenovirus, had increased proliferation of LPCs. Signal transducer and activator of transcription (STAT) 3, a component of the IL-22 signaling pathway, was activated in LPCs isolated from DDC-fed IL-22TG mice. Deletion of STAT3 from livers of IL-22TG mice reduced proliferation of LPCs. In addition, the receptors IL-22R1 and IL-10R2 were detected on epithelial cell adhesion molecule(+)CD45(-) LPCs isolated from DDC-fed wild-type mice. Culture of these cells with IL-22 activated STAT3 and led to cell proliferation, but IL-22 had no effect on proliferation of STAT3-deficient EpCAM(+)CD45(-) LPCs. IL-22 also activated STAT3 and promoted proliferation of cultured BMOL cells (a mouse LPC line).
In livers of mice and patients with chronic HBV infection, inflammatory cells produce IL-22, which promotes proliferation of LPCs via STAT3. These findings link inflammation with proliferation of LPCs in patients with HBV infection.
在慢性乙型肝炎病毒（HBV）感染患者的肝脏炎症区域，常观察到肝干细胞/祖细胞（LPCs）的增殖，这些细胞可分化为肝细胞或胆管上皮细胞。我们研究了炎症如何促进 LPCs 的增殖。
我们检测了白细胞介素（IL）-22 在慢性 HBV 感染患者和小鼠 LPCs 增殖中的作用。IL-22 是一种肝细胞存活因子，通过给予含有 3,5-二乙氧基羰基-1,4-二氢吡啶（DDC）的饮食来诱导小鼠 LPCs 的增殖。
HBV 感染患者肝组织中 IL-22 的表达增加，且与炎症程度和 LPCs 的增殖相关。在肝中特异性过表达 IL-22 的转基因小鼠（IL-22TG）或感染表达 IL-22 的腺病毒的 DDC 饮食小鼠，其 LPCs 的增殖增加。DDC 饮食喂养的 IL-22TG 小鼠分离的 LPCs 中信号转导和转录激活因子（STAT）3 被激活，STAT3 是 IL-22 信号通路的一个组成部分。从 IL-22TG 小鼠肝脏中删除 STAT3 可减少 LPCs 的增殖。此外，在从 DDC 饮食喂养的野生型小鼠中分离的上皮细胞黏附分子（EpCAM）+CD45- LPCs 上检测到 IL-22R1 和 IL-10R2 受体。用 IL-22 培养这些细胞可激活 STAT3 并导致细胞增殖，但 IL-22 对 STAT3 缺陷的 EpCAM+CD45- LPCs 的增殖没有影响。IL-22 还可激活 STAT3 并促进培养的 BMOL 细胞（一种小鼠 LPC 系）的增殖。
在慢性 HBV 感染小鼠和患者的肝脏中，炎症细胞产生 IL-22，通过 STAT3 促进 LPCs 的增殖。这些发现将炎症与 HBV 感染患者的 LPCs 增殖联系起来。
