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: 9155440
• 负责人: bin gao
• 金额: $ 101.47万
• 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/9155440
• 关键词: Ablation; Acute; Address; Affect; Bacterial Infections; Bacterial Translocation; Biological Assay; Blood Glucose; Cells; Chronic; Concanavalin A; Diet; Dose; Enteral; Escherichia coli; Exhibits; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Gelatinase A; Genes; Genetic; Goals; Hepatic; Hepatocyte; Host Defense; Human; Immune; In Vitro; Infection; Insulin; Insulin Resistance; Interleukin 6 Receptor; Interleukin-6; Klebsiella pneumonia bacterium; Knock-out; Laboratories; Liver; Liver Regeneration; Liver diseases; Mediating; Mesentery; Metabolic; Metabolic syndrome; Mus; Natural Immunity; Natural regeneration; Obesity; Organ; Partial Hepatectomy; Pathogenesis; Play; Pneumonia; Predisposition; Production; Promoter Regions; Proteins; Recombinants; Recruitment Activity; Resistance; Role; STAT3 gene; Serum; Signal Pathway; Signal Transduction; Source; Streptozocin; Transgenic Mice; Work; antimicrobial; cell type; chromatin immunoprecipitation; chronic liver disease; cytokine; feeding; glucose metabolism; glucose production; hepatic gluconeogenesis; in vivo; interleukin 20; interleukin-22; killer T cell; liver inflammation; liver injury; liver repair; lymph nodes; microbial; neutrophil; pathogen; response; tissue repair; tumor

Innate immunity and cytokines in liver disease: 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 (1) Liver is the major source of elevated serum lipocalin-2 levels after bacterial infection or partial hepatectomy; (2) Biologically active, high levels of interleukin-22 inhibit hepatic gluconeogenesis but do not affect obesity and its metabolic consequences. Liver is the major source of elevated serum lipocalin-2 levels after bacterial infection or partial hepatectomy: a critical role for IL-6/STAT3. Lipocalin-2 (LCN2) was originally isolated from human neutrophils and termed neutrophil gelatinase-associated lipocalin (NGAL). However, the functions of LCN2 and the cell types that are primarily responsible for LCN2 production remain unclear. To address these issues, hepatocyte-specific Lcn2 knockout (Lcn2(Hep-/-)) mice were generated and subjected to bacterial infection (with Klesbsiella pneumoniae or Escherichia coli) or partial hepatectomy (PHx). Studies of Lcn2(Hep-/-) mice revealed that hepatocytes contributed to 25% of the low basal serum level of LCN2 protein (∼ 62 ng/mL) but were responsible for more than 90% of the highly elevated serum LCN2 protein level (∼ 6,000 ng/mL) postinfection and more than 60% post-PHx (∼ 700 ng/mL). Interestingly, both Lcn2(Hep-/-) and global Lcn2 knockout (Lcn2(-/-)) mice demonstrated comparable increases in susceptibility to infection with K. pneumoniae or E. coli. These mice also had increased enteric bacterial translocation from the gut to the mesenteric lymph nodes and exhibited reduced liver regeneration after PHx. Treatment with interleukin (IL)-6 stimulated hepatocytes to produce LCN2 in vitro and in vivo. Hepatocyte-specific ablation of the IL-6 receptor or Stat3, a major downstream effector of IL-6, markedly abrogated LCN2 elevation in vivo. Furthermore, chromatin immunoprecipitation (ChIP) assay revealed that STAT3 was recruited to the promoter region of the Lcn2 gene upon STAT3 activation by IL-6. Conclusion: Hepatocytes are the major cell type responsible for LCN2 production after bacterial infection or PHx, and this response is dependent on IL-6 activation of the STAT3 signaling pathway. Thus, hepatocyte-derived LCN2 plays an important role in inhibiting bacterial infection and promoting liver regeneration. Biologically active, high levels of interleukin-22 inhibit hepatic gluconeogenesis but do not affect obesity and its metabolic consequences. Interleukin-22 (IL-22), a cytokine with important functions in anti-microbial defense and tissue repair, has been recently suggested to have beneficial effects in obesity and metabolic syndrome in some but not in other studies. Here, we re-examined the effects of IL-22 on obesity, insulin resistance, and hepatic glucose metabolism.Genetic deletion of IL-22 did not affect high-fat-diet (HFD)-induced obesity and insulin resistance. IL-22 transgenic mice with relatively high levels of circulating IL-22 (600 pg/ml) were completely resistant to Concanavalin A-induced liver injury but developed the same degree of high fat diet (HFD)-induced obesity, insulin resistance, and fatty liver as the wild-type littermate controls. Similarly, chronic treatment with recombinant mouse IL-22 (rmIL-22) protein did not affect HFD-induced obesity and the associated metabolic syndrome. In vivo treatment with a single dose of rmIL-22 downregulated the hepatic expression of gluconeogenic genes and subsequently inhibited hepatic gluconeogenesis and reduced blood glucose levels both in HFD-fed and streptozotocin (STZ)-treated mice without affecting insulin production. In vitro exposure of mouse primary hepatocytes to IL-22 suppressed glucose production and the expression of gluconeogenic genes. These inhibitory effects were partially reversed by blocking STAT3 or the AMPK signaling pathway. Conclusion: Biologically active, high levels of IL-22 do not affect obesity and the associated metabolic syndrome. Acute treatment with IL-22 inhibits hepatic gluconeogenesis, which is mediated via the activation of STAT3 and AMPK in hepatocytes.

先天免疫和肝病的细胞因子： 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，我们已经证明了（1）肝脏是细菌感染或部分肝切除术后血清脂蛋白-2水平升高的主要来源； （2）生物活性，高水平的白介素22抑制肝糖异生，但不会影响肥胖及其代谢后果。 肝脏是细菌感染或部分肝切除术后血清Lipocalin-2水平升高的主要来源：IL-6/STAT3的关键作用。 最初从人类嗜中性粒细胞中分离出Lipocalin-2（LCN2），并称为中性粒细胞明胶酶相关的Lipocalin（NGAL）。但是，LCN2的功能和主要负责LCN2产生的细胞类型尚不清楚。为了解决这些问题，产生了肝细胞特异性LCN2敲除（LCN2（HEP-/ - ））小鼠，并经受细菌感染（伴有肺炎Klesbsiella肺炎或大肠杆菌）或部分肝切除术（PHX）。 LCN2（HEP - / - ）小鼠的研究表明，肝细胞占LCN2蛋白基底血清水平的25％（〜62 ng/ml），但在高度升高的血清LCN2蛋白水平（〜6,000 ng/ml）的高度升高（〜6,000 ng/ml）和60％的post-nefect和60％的puspe-phecn和60％的phectecn和60％。有趣的是，LCN2（HEP - / - ）和全球LCN2敲除（LCN2（ - / - ））小鼠均表现出可比的肺炎或大肠杆菌感染的易感性。这些小鼠还增加了肠细菌从肠道到肠系膜淋巴结的易位，并在PHX后表现出降低的肝脏再生。用白介素（IL）-6刺激的肝细胞在体外和体内产生LCN2。 IL-6受体或STAT3的肝细胞特异性消融，IL-6的主要下游效应子显着废除了体内LCN2升高。此外，染色质免疫沉淀（芯片）测定表明，在IL-6激活STAT3激活后，将STAT3募集到LCN2基因的启动子区域。结论：肝细胞是细菌感染或PHX后负责LCN2产生的主要细胞类型，此反应取决于STAT3信号通路的IL-6激活。因此，肝细胞衍生的LCN2在抑制细菌感染和促进肝脏再生方面起着重要作用。 生物活性，高水平的白介素22抑制肝糖异生，但不会影响肥胖及其代谢后果。 白介素-22（IL-22）是一种在抗微生物防御和组织修复中具有重要功能的细胞因子，最近被认为在某些研究中对肥胖和代谢综合征具有有益作用，但在其他研究中没有。在这里，我们重新检查了IL-22对肥胖，胰岛素抵抗和肝葡萄糖代谢的影响。IL-22的遗传缺失不会影响高脂 - 含量（HFD）诱导的肥胖和胰岛素抵抗。具有相对较高水平的循环IL-22（600 pg/ml）的IL-22转基因小鼠完全抗凝乳蛋白乳蛋白乳蛋白乳蛋白乳蛋白A诱导的肝损伤，但产生了相同程度的高脂肪饮食（HFD）诱导的肥胖，胰岛素抵抗和脂肪肝，与野生型乱翅其控制。同样，重组小鼠IL-22（RMIL-22）蛋白的慢性治疗不会影响HFD诱导的肥胖症和相关的代谢综合征。用单剂量的RMIL-22进行体内处理，下调了糖原性基因的肝表达，随后抑制了HFD喂养的HFD喂养和链链球菌素（STZ）（STZ）所处理的小鼠的肝糖生成，并降低了血糖水平，而不会影响胰岛素的产生。小鼠原发性肝细胞对IL-22的体外暴露抑制了葡萄糖的产生和糖原性基因的表达。这些抑制作用通过阻止STAT3或AMPK信号通路来部分逆转。结论：生物活性，高水平的IL-22不影响肥胖症和相关的代谢综合征。用IL-22急性治疗抑制肝糖异生，通过在肝细胞中STAT3和AMPK的激活介导。