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: 8746471
• 负责人: bin gao
• 金额: $ 127.82万
• 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/8746471
• 关键词: Ablation; Acute; Affect; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Attenuated; Biological Assay; Cell Count; Cell Line; Cell Proliferation; Cells; Choline; Clinical Treatment; Clinical Trials; Coculture Techniques; Diet; Ethionine; Feedback; Fibrosis; Genetic; Goals; Hepatic Stellate Cell; Hepatitis; Hepatitis B Virus; Host Defense; IFNGR1 gene; IRF1 gene; Immune; In Vitro; Infection; Inflammation; Injection of therapeutic agent; Interferon Type II; Interferons; Interleukin 4 Receptor; Interleukin-4; Knock-out; Knockout Mice; Laboratories; Liver; Liver Fibrosis; Liver Regeneration; Liver diseases; Macrophage Activation; Malignant neoplasm of liver; Mediating; Modeling; Modification; Mus; Natural Immunity; Neutrophil Infiltration; Organ; Pathogenesis; Patients; Play; Production; Regulation; Reporting; Role; STAT1 gene; STAT3 gene; STAT6 Transcription Factor; Signal Transduction; Signaling Molecule; Staining method; Stains; Stem cells; Viral hepatitis; Wild Type Mouse; alpha-galactosylceramide; attenuation; chronic liver disease; cytokine; dietary supplements; feeding; improved; in vivo; interferon gamma receptor; interferon gamma receptors; interleukin-22; killer T cell; liver inflammation; liver injury; liver repair; microbial; neutrophil; 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) that invariant NKT cell activation induces neutrophil accumulation and hepatitis and (2) that IFN- inhibits liver progenitor cell proliferation in HBV-infected patients and in 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-fed mice. Invariant NKT cell activation induces neutrophil accumulation and hepatitis: Opposite regulation by IL-4 and IFN-gamma: Alpha-Galactosylceramide (alpha-Galcer), a specific agonist for invariant natural killer T (iNKT) cells, is being evaluated in clinical trials for the treatment of viral hepatitis and liver cancer. However, the results from alpha-Galcer treatment are mixed, partially because of the variety of cytokines produced by activated iNKT cells that have an unknown synergistic effect on the progression of liver disease. It is well documented that injection of alpha-Galcer induces mild hepatitis with a rapid elevation in the levels of interleukin (IL)-4 and a delayed elevation in the levels of interferon-gamma (IFN-gamma), and both of these cytokines are thought to mediate many functions of iNKT cells. Surprisingly, during this reporting period, we have demonstrated that genetic deletion of both IL-4 and IFN-gamma aggravated, rather than abolished, alpha-Galcer-induced iNKT hepatitis. Moreover, genetic ablation of IL-4, the IL-4 receptor, or its downstream signaling molecule signal transducer and activator of transcription (STAT)6 ameliorated alpha-Galcer-induced neutrophil infiltration, liver injury, and hepatitis. In contrast, genetic deletion of IFN-gamma, the IFN-gamma receptor, or its downstream signaling molecule STAT1 enhanced liver neutrophil accumulation, thereby exacerbating liver injury and hepatitis. Moreover, depletion of neutrophils eradicated alpha-Galcer-induced liver injury in wild-type, STAT1 knockout, and IFN-gamma knockout mice. Conclusion: Our results propose a model in which activated iNKT cells rapidly release IL-4, which promotes neutrophil survival and hepatitis but also sequentially produce IFN-gamma, which acts in a negative feedback loop to ameliorate iNKT hepatitis by inducing neutrophil apoptosis. Thus, modification of iNKT production of IL-4 and IFN-gamma may have the potential to improve the efficacy of alpha-Galcer in the treatment of liver disease. IFN-gamma inhibits liver progenitor cell proliferation in HBV-infected patients and in 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-fed mice. Proliferation of liver progenitor cells (LPCs) is associated with inflammation and fibrosis in chronic liver diseases. However, how inflammation and fibrosis affect LPCs remains obscure. During this reporting period, we examined the role of interferon (IFN)-gamma, an important pro-inflammatory and anti-fibrotic cytokine, in LPC expansion in HBV-infected patients and in mice challenged with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- or choline-deficient, ethionine-supplemented (CDE) diet as well as in primary LPCs and LPC cell line. We have demonstrated that the CK19 staining scores correlated with inflammation and fibrosis grades in the livers from 110 HBV-infected patients. Nine-month IFN-gamma treatment decreased LPC numbers, inflammation, and fibrosis in these HBV-infected patients. Similarly, a two-week IFN-gamma treatment also decreased LPC activation in DDC-treated mice. Disruption of IFN-gamma or its signaling components (e.g., IFNGR, STAT1, and IRF-1) increased LPC proliferation and liver fibrosis in DDC-fed mice. In contrast, deletion of IFN-gamma did not increase, but rather slightly reduced LPC proliferation in CDE-fed mice. In vitro, IFN-gamma attenuated proliferation of the LPC cell line BMOL and of primary LPCs from wild type mice, but not STAT1-/- or IRF-1-/- mice. Furthermore, co-culture assays suggest that IFN-gamma can indirectly promote LPC proliferation via the activation of macrophages but attenuate it via the inhibition of hepatic stellate cells. In conclusion: IFN-gamma inhibits LPC expansion via the direct inhibition of LPC proliferation and indirect attenuation of liver fibrosis in the DDC model, but it may also enhance LPC expansion via the promotion of inflammation in the CDE model; thereby playing dual roles in regulating LPC proliferation in vivo.

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）不变的NKT细胞激活会诱导中性粒细胞的积累和肝炎，并且（2）IFN- IFN- IFN-抑制了HBV感染的患者的肝脏祖细胞增殖，在3,5-5-5-二甲氧基氧基1,4-二甲基1,4-二二甲基饮食中。 不变的NKT细胞激活诱导中性粒细胞的积累和肝炎：IL-4和IFN-Gamma的相反调节： 在临床试验中评估了一种不变天然杀伤剂T（INKT）细胞的特定激动剂（一种特定的激动剂）α-甲乳糖基酶（Alpha-galcer），以治疗病毒性肝炎和肝癌的治疗。然而，α-盖尔治疗的结果是混合的，部分是由于激活的inkt细胞产生的各种细胞因子对肝病的进展有未知的协同作用。有充分的文献证明，注射α-galcer会诱导轻度肝炎，并在白介素（IL）-4的水平迅速升高，并且延迟的升高延迟的升高（IFN-GAMMA）（IFN-GAMMA）水平，并且这两种细胞因子都被认为可以介导INKT细胞的许多功能。令人惊讶的是，在此报告期间，我们已经证明了IL-4和IFN-Gamma的遗传缺失加剧而不是废除α-盖尔诱导的INKT肝炎。此外，IL-4的遗传消融，IL-4受体或其下游信号分子信号传感器和转录的激活因子（STAT）6改善了α-甲氧甲酶诱导的嗜中性粒细胞浸润，肝损伤和肝炎。相反，IFN-gamma，IFN-GAMMA受体或其下游信号传导分子Stat1的遗传缺失增强了肝脏中性粒细胞的积累，从而加剧了肝损伤和肝炎。此外，中性粒细胞消除了野生型，STAT1敲除和IFN-gamma敲除小鼠的α-盖尔 - 盖尔 - 盖尔诱导的肝损伤。结论：我们的结果提出了一个模型，其中激活的Inkt细胞迅速释放IL-4，该模型促进了中性粒细胞存活和肝炎，但也依次产生IFN-GAMMA，该模型在负反馈回路中起作用，以通过诱导中性粒细胞凋亡来缓解肝炎。因此，对IL-4和IFN-GAMMA的INKT产生的修饰可能有可能提高α-甲壳虫在治疗肝病治疗方面的疗效。 IFN-GAMMA抑制了HBV感染患者的肝脏祖细胞增殖，3,5-二甲氧基碳酸1,4-二氢核苷饮食中饮食中饮食中的小鼠中抑制了肝脏祖细胞的增殖。 肝脏祖细胞（LPC）的增殖与慢性肝病的炎症和纤维化有关。但是，炎症和纤维化如何影响LPC仍然晦涩。 During this reporting period, we examined the role of interferon (IFN)-gamma, an important pro-inflammatory and anti-fibrotic cytokine, in LPC expansion in HBV-infected patients and in mice challenged with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- or choline-deficient, ethionine-supplemented (CDE) diet as well as在主要的LPC和LPC细胞系中。我们已经证明，CK19染色评分与110名HBV感染患者的肝脏的炎症和纤维化等级相关。这些HBV感染的患者的LPC数量，炎症和纤维化减少了9个月的IFN-GAMMA治疗。同样，为期两周的IFN-gamma处理也降低了DDC处理的小鼠的LPC激活。 IFN-GAMMA或其信号传导成分（例如IFNGR，STAT1和IRF-1）的破坏增加了DDC喂养小鼠的LPC增殖和肝纤维化。相比之下，IFN-gamma的缺失并没有增加，而是在CDE喂养的小鼠中略有减少的LPC增殖。在体外，IFN-gamma减弱了野生型小鼠的LPC细胞系BMOL和原发性LPC的增殖，但不是STAT1 - / - 或IRF-1 - / - 小鼠的增殖。此外，共培养分析表明，IFN-gamma可以通过激活巨噬细胞间接促进LPC增殖，但通过抑制肝星状细胞来减弱它。总之：IFN-GAMMA通过直接抑制LPC增殖和DDC模型中肝纤维化的间接衰减来抑制LPC的扩展，但它也可能通过促进CDE模型中的炎症来增强LPC的扩展；从而在体内调节LPC扩散中扮演双重角色。