Innate immunity and cytokines in liver disease

肝损伤、炎症和修复中的天然免疫和细胞因子 肝脏是一个具有较强先天免疫的器官，在宿主防御微生物感染和肿瘤转化中起着重要作用。新出现的证据表明，先天免疫以及由先天免疫细胞产生的各种细胞因子也有助于急性和慢性肝病的发病机制。本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。在本财政年度，我们已经证明：（1）肝脏和骨髓STAT 3的相互作用通过调节先天免疫在促进肝脏再生中起着重要作用;（2）四氯化碳诱导的肝脏炎症和肝细胞损伤在骨髓细胞特异性STAT 3基因敲除小鼠中是分离的。 肝脏和骨髓STAT 3相互作用通过调节天然免疫促进肝再生 三分之二部分肝切除术引发的肝再生伴随着肝内毒素水平升高，这有助于再生过程，但肝脏炎症和细胞凋亡仍然矛盾地有限。在这里，我们表明，信号转导和转录激活因子3（STAT 3），一个重要的抗炎信号，在部分肝切除术后髓样细胞中被激活，其条件性缺失导致炎症反应增强。令人惊讶的是，这伴随着改善的而不是受损的再生反应，肝脏STAT 3活化增加，这可能有助于增强肝脏再生。事实上，肝细胞和骨髓细胞中STAT 3的条件性缺失导致STAT 1活化和肝细胞凋亡的升高，以及部分肝切除术后存活率的显著降低，而STAT 1的额外整体缺失可保护免受这些影响。结论：骨髓和肝脏STAT 3信号传导的相互作用对于通过缓和由STAT 1信号传导介导的强烈先天性炎症反应来预防肝再生期间的肝衰竭是必不可少的。 骨髓细胞特异性STAT 3基因敲除小鼠中四氯化碳诱导的肝脏炎症与肝细胞损伤之间的分离 肝损伤与炎症有关，通常认为炎症会加速肝脏疾病的进展;然而，临床数据显示，在某些患者中，炎症并不总是与肝细胞损伤相关。使用实验动物模型研究这些事件背后的细胞机制，我们发现炎症可以减轻骨髓特异性信号转导子和转录激活子3（STAT 3）敲除小鼠中四氯化碳（CCl（4））诱导的肝坏死。作为一种重要的抗炎信号，骨髓细胞中STAT 3的条件性缺失导致CCl（4）注射后肝脏炎症显著增强。然而，这些作用也伴随着肝坏死减少，与血清白细胞介素-6（IL-6）和肝STAT 3活化升高相关。在骨髓特异性STAT 3敲除小鼠中，肝细胞中STAT 3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STAT 3激活减弱了骨髓特异性STAT 3敲除小鼠中由CCl（4）诱导的肝细胞损伤，表明与激活肝STAT 3的保肝细胞因子优势相关的炎症可能减少而不是加速慢性肝病患者的肝细胞损伤。

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.