Innate immunity and cytokines in liver disease

肝病中的先天免疫和细胞因子

• 批准号: 8148175
• 负责人: bin gao
• 金额: $ 82.28万
• 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/8148175
• 关键词: Liver diseases; Natural Immunity; cytokine

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) interplay of hepatic and myeloid STAT3 plays an important role in facilitating liver regeneration via tempering innate immunity; (2) liver inflammation and hepatocellular damage induced by carbon tetrachloride are dissociated in myeloid cell-specific STAT 3 gene knockout mice. Interplay of hepatic and myeloid STAT3 in facilitating liver regeneration via tempering innate immunity Liver regeneration triggered by two-thirds partial hepatectomy is accompanied by elevated hepatic levels of endotoxin, which contributes to the regenerative process, but liver inflammation and apoptosis remain paradoxically limited. Here, we show that signal transducer and activator of transcription 3 (STAT3), an important anti-inflammatory signal, is activated in myeloid cells after partial hepatectomy and its conditional deletion results in an enhanced inflammatory response. Surprisingly, this is accompanied by an improved rather than impaired regenerative response with increased hepatic STAT3 activation, which may contribute to the enhanced liver regeneration. Indeed, conditional deletion of STAT3 in both hepatocytes and myeloid cells results in elevated activation of STAT1 and apoptosis of hepatocytes, and a dramatic reduction in survival after partial hepatectomy, whereas additional global deletion of STAT1 protects against these effects. Conclusion: An interplay of myeloid and hepatic STAT3 signaling is essential to prevent liver failure during liver regeneration through tempering a strong innate inflammatory response mediated by STAT1 signaling. Dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell-specific STAT 3 gene knockout mice. Liver injury is associated with inflammation, which is generally believed to accelerate the progression of liver diseases; however, clinical data show that inflammation does not always correlate with hepatocelluar damage in some patients. Investigating the cellular mechanisms underlying these events using an experimental animal model, we show that inflammation may attenuate liver necrosis induced by carbon tetrachloride (CCl(4)) in myeloid-specific signal transducer and activator of transcription 3 (STAT3) knockout mice. As an important anti-inflammatory signal, conditional deletion of STAT3 in myeloid cells results in markedly enhanced liver inflammation after CCl(4) injection. However, these effects are also accompanied by reduced liver necrosis, correlating with elevated serum interleukin-6 (IL-6) and hepatic STAT3 activation. An additional deletion of STAT3 in hepatocytes in myeloid-specific STAT3 knockout mice restored hepatic necrosis but decreased liver inflammation. CONCLUSION: Inflammation-mediated STAT3 activation attenuates hepatocellular injury induced by CCl(4) in myeloid-specific STAT3 knockout mice, suggesting that inflammation associated with a predominance of hepatoprotective cytokines that activate hepatic STAT3 may reduce rather than accelerate hepatocellular damage in patients with chronic liver diseases.

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）肝和髓样STAT3的相互作用在通过回火先天免疫来促进肝脏再生方面起着重要作用； （2）四氯化碳诱导的肝炎和肝细胞损伤在髓样细胞特异性STAT 3基因敲除小鼠中分离。 肝和髓样STAT3的相互作用在促进肝脏再生中通过回火先天免疫 由三分之二的部分肝切除术引发的肝脏再生伴随着肝毒素水平升高，这有助于再生过程，但是肝炎和凋亡仍然矛盾地有限。在这里，我们表明，转录3（STAT3）是一种重要的抗炎信号的信号传感器和激活因子，在部分肝切除术后在髓样细胞中激活，其条件缺失导致炎症反应增强。令人惊讶的是，这伴随着改善而不是再生反应，而肝脏STAT3激活增加，这可能有助于增强的肝脏再生。实际上，肝细胞和髓样细胞中Stat3的有条件缺失导致STAT1激活和肝细胞凋亡的激活升高，部分肝切除术后生存的生存率急剧降低，而STAT1的其他全球删除量则具有额外的全球缺失。结论：髓样和肝脏STAT3信号的相互作用对于防止由STAT1信号传导介导的强烈的先天炎症反应来防止肝脏再生期间的肝衰竭。 髓样细胞特异性STAT 3基因基因敲除小鼠，四氯化碳诱导的肝炎和肝细胞损伤之间的解离。 肝损伤与炎症有关，通常认为这会加速肝病的进展。但是，临床数据表明，炎症并不总是与某些患者的肝素损伤相关。通过实验动物模型研究了这些事件的细胞机制，我们表明炎症可能会减弱四氯化碳（CCL（4））在转录3（STAT3）基因敲除小鼠中诱导的肝坏死（CCL（4））。作为一个重要的抗炎信号，髓样细胞中Stat3的条件缺失导致CCL（4）注射后肝炎显着增强。但是，这些作用还伴随着肝坏死的降低，与血清白介素-6（IL-6）和肝Stat3激活相关。在髓样特异性STAT3敲除小鼠中，STAT3在肝细胞中的额外缺失恢复了肝坏死，但减少了肝脏炎症。结论：炎症介导的STAT3激活减轻了CCL（4）在髓样特异性STAT3敲除小鼠中诱导的肝细胞损伤，这表明与肝细胞因子占主导性肝细胞因子相关的炎症可激活肝Stat3的肝癌细胞因子，而不是降低肝细胞损伤的肝细胞损伤，而不是炎症患者患有炎症性损伤。