Innate immunity and cytokines in liver diseases

肝脏疾病中的先天免疫和细胞因子

• 批准号: 8559263
• 负责人: bin gao
• 金额: $ 110.01万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8559263
• 关键词: Acute; Adenoviruses; Apoptosis; Biliary; Binding; Cell Adhesion Molecules; Cell Aging; Cell Line; Cell Proliferation; Cells; Chronic Hepatitis B; Cultured Cells; Cytokine Inducible SH2-Containing Protein; Diet; Epithelial Cells; Gene Targeting; Goals; Hepatic; Hepatic Fibrogenesis; Hepatic Stellate Cell; Hepatitis B; Hepatitis B Virus; Hepatocyte; Host Defense; Human; Immune; Immunity; Immunoprecipitation; In Vitro; Infection; Inflammation; Inflammatory; Injury; Interleukin Receptor; Interleukins; Laboratories; Link; Liver; Liver Fibrosis; Liver Regeneration; Liver diseases; Mediating; Mus; Natural Immunity; Organ; PTPRC gene; Pathogenesis; Pathway interactions; Patients; Play; Recovery; Resolution; Role; STAT3 gene; Signal Pathway; Signal Transduction; Smooth Muscle Actin Staining Method; Stat3 protein; Stem cells; Surface; TACSTD2 gene; Transgenes; Transgenic Mice; Wild Type Mouse; antimicrobial; beta-Galactosidase; cell type; chronic liver disease; cytokine; feeding; in vivo; injury and repair; interleukin-22; killer T cell; microbial; overexpression; prevent; repaired; response; senescence; stem; tissue repair; tumor

Innate immunity and cytokines in liver injury, inflammation, and repair The liver is an organ with strong innate immunity, which plays an important role in host defense against microbial infection and tumor transformation. Emerging evidence suggests that innate immunity as well as a variety of cytokines produced by innate immune cells also contribute to the pathogenesis of acute and chronic liver diseases. Our laboratory has been actively studying the role of innate immunity and its associated cytokines in liver injury and repair. During the fiscal year, we have demonstrated that (1) IL-22 promotes liver progenitor cell proliferation and (2) IL-22 inhibits liver fibrosis by inducing hepatic stellate cell senescence. Interleukin-22 promotes proliferation of liver stem/progenitor cells in mice and patients with chronic hepatitis B virus infection. 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. During this fiscal year, 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). Our findings suggest that 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. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Interleukin (IL)-22 is known to play a key role in promoting antimicrobial immunity, inflammation, and tissue repair at barrier surfaces by binding to the receptors, IL-10R2 and IL-22R1. IL-22R1 is generally thought to be expressed exclusively in epithelial cells. In this study, we identified high levels of IL-10R2 and IL-22R1 expression on hepatic stellate cells (HSCs), the predominant cell type involved in liver fibrogenesis in response to liver damage. In vitro treatment with IL-22 induced the activation of signal transducer and activator of transcription (STAT) 3 in primary mouse and human HSCs. IL-22 administration prevented HSC apoptosis in vitro and in vivo, but surprisingly, the overexpression of IL-22 by either gene targeting (e.g., IL-22 transgenic mice) or exogenous administration of adenovirus expressing IL-22 reduced liver fibrosis and accelerated the resolution of liver fibrosis during recovery. Furthermore, IL-22 overexpression or treatment increased the number of senescence-associated beta-galactosidase-positive HSCs and decreased alpha-smooth muscle actin expression in fibrotic livers in vivo and cultured HSCs in vitro. Deletion of STAT3 prevented IL-22-induced HSC senescence in vitro, whereas the overexpression of a constitutively activated form of STAT3 promoted HSC senescence through p53- and p21-dependent pathways. Finally, IL-22 treatment up-regulated the suppressor of cytokine signaling (SOCS) 3 expression in HSCs. Immunoprecipitation analyses revealed that SOCS3 bound p53 and subsequently increased the expression of p53 and its target genes, contributing to IL-22-mediated HSC senescence. Conclusion: IL-22 induces the senescence of HSCs, which express both IL-10R2 and IL-22R1, thereby ameliorating liver fibrogenesis. The antifibrotic effect of IL-22 is likely mediated by the induction of HSC senescence, in addition to the previously discovered hepatoprotective functions of IL-22.

肝损伤，炎症和修复中的先天免疫和细胞因子 肝脏是具有强大先天免疫力的器官，在宿主防御微生物感染和肿瘤转化中起着重要作用。新兴证据表明，先天免疫以及先天免疫细胞产生的多种细胞因子也有助于急性和慢性肝病的发病机理。我们的实验室一直在积极研究先天免疫及其相关细胞因子在肝损伤和修复中的作用。在财政年度，我们已经证明（1）IL-22促进肝脏祖细胞增殖，（2）IL-22通过诱导肝星状细胞衰老来抑制肝纤维化。 白介素22促进小鼠肝干/祖细胞的增殖和慢性乙型肝炎病毒感染的患者。 肝干/祖细胞（LPC）的增殖可以区分为肝细胞或胆道上皮细胞，通常在患者的肝脏肝脏慢性发炎区域中观察到。我们研究了炎症如何促进LPC的扩散。在这个财政年度，我们研究了白介素（IL）-22（肝细胞生存因子）对LPC在慢性乙型肝炎病毒（HBV）感染和小鼠中LPC的增殖的作用。通过喂养含有3,5-二甲氧甲苄酮1,4-二氢核苷（DDC）的饮食来诱导小鼠LPC的扩散。 HBV患者的IL-22的肝表达增加，与LPC的炎症和增殖等级相关。在DDC饮食中过表达IL-22转基因（IL-22TG）或用表达IL-22表达IL-22的腺病毒感染的小鼠，LPC的增殖增加了。在从DDC喂养的IL-22TG小鼠中分离出的LPC中，在IL-22信号途径的一个成分（STAT）3（Stat）3（Stat）3（Stat）3的信号转换器（Stat）3。从IL-22TG小鼠肝脏中的STAT3删除减少了LPC的增殖。另外，从DDC喂养的野生型小鼠中分离出的上皮细胞粘附分子（+）CD45（ - ）LPC上检测到受体IL-22R1和IL-10R2。这些用IL-22的细胞培养激活了STAT3并导致细胞增殖，但IL-22对Stat3缺陷型EPCAM（+）CD45（ - ）LPC的增殖没有影响。 IL-22还激活了STAT3并促进了培养的BMOL细胞（小鼠LPC系）的增殖。我们的发现表明，在小鼠肝脏和患有慢性HBV感染的患者中，炎性细胞会产生IL-22，从而通过STAT3促进LPC的增殖。这些发现将炎症与HBV感染患者中LPC的增殖联系起来。 白介素22诱导肝星状细胞衰老并限制小鼠的肝纤维化。 众所周知，白介素（IL）-22在通过与受体IL-10R2和IL-22R1结合，在促进屏障表面的抗菌免疫，炎症和组织修复方面起着关键作用。通常认为IL-22R1仅在上皮细胞中表达。在这项研究中，我们在肝星状细胞（HSC）上鉴定了高水平的IL-10R2和IL-22R1表达，这是对肝纤维发生涉及的主要细胞类型，响应肝纤维发生响应肝损伤。用IL-22的体外处理诱导了原代小鼠和人类HSC中的信号传感器和转录活化剂（Stat）3的激活。 IL-22给药可预防体外和体内HSC凋亡，但令人惊讶的是，通过基因靶向（例如IL-22转基因小鼠）对IL-22的过表达或表达IL-22的腺病毒降低肝纤维化并加速了回收液体纤维的分辨率。此外，IL-22的过表达或治疗增加了与衰老相关的β-半乳糖苷酶阳性HSC的数量，并减少了体内纤维化肝脏中α-光滑的肌肉肌动蛋白的表达，体内和体外培养的HSCS。 STAT3的缺失阻止了IL-22诱导的HSC体外衰老，而STAT3组成型激活形式的过表达通过p53-和p21依赖性途径促进了HSC衰老。最后，IL-22处理上调了HSC中细胞因子信号传导（SOCS）3表达的抑制。免疫沉淀分析表明，SOCS3结合的p53并随后增加了p53及其靶基因的表达，这有助于IL-22介导的HSC衰老。结论：IL-22诱导了表达IL-10R2和IL-22R1的HSC的衰老，从而改善了肝纤维发生。除先前发现的IL-22的肝保护功能外，IL-22的抗纤维化作用可能是HSC衰老的诱导介导的。