An inhibitor of interleukin-6 trans-signalling, sgp130, contributes to impaired acute phase response in human chronic liver disease
An inhibitor of interleukin-6 trans-signalling, sgp130, contributes to impaired acute phase response in human chronic liver disease
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DOI：
10.1111/j.1365-2249.2009.03916.x
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发表时间：
2009-06-01
影响因子：
4.6
通讯作者：
Deviere, J.
中科院分区：
文献类型：
--
作者：
Lemmers, A.;Gustot, T.;Deviere, J.
在慢性肝病中，高循环白细胞介素（IL）-6与不良的急性期反应形成对比。我们评估了慢性肝病中肝脏和循环IL-6受体（IL-6 R）形式对IL-6生物活性的影响。检测了45例酒精性肝病患者、84例经颈静脉肝活检的丙型肝炎病毒（HCV）感染患者和15例健康人血浆中IL-6、可溶性IL-6受体和sgp 130水平。对54例酒精性肝病伴或不伴肝硬化患者和18例HCV感染患者的肝提取物进行IL-6 R mRNA定量。在肝细胞培养物上评价gp 130-Fc对由IL-6反式信号传导诱导的纤维蛋白原分泌的影响。血浆IL-6和sgp 130水平随着慢性肝病的分期而升高，并与疾病严重程度显着相关，但可溶性IL-6 R水平不随慢性肝病的分期而升高。酒精性肝病患者血浆IL-6水平高于丙型肝炎患者，但肝脏IL-6 R表达低于丙型肝炎患者。在酒精性和HCV相关性肝病中，肝脏IL-6 R表达随纤维化进展而降低。在体外，在肝细胞上，gp 130-Fc钝化急性期反应，而可溶性IL-6 R增强IL-6刺激。在晚期慢性肝病中，高血浆IL-6与低肝脏IL-6 R表达相关。这种情况使得高血浆sgp 130能够充当肝脏IL-6反式信号传导的主要负调节剂，如本文在肝细胞上的功能所示。这可能解释了慢性肝病中IL-6诱导的不良急性期反应。
In chronic liver disease, high circulating interleukin (IL)-6 contrasts with a poor acute phase response. We evaluated the impact of liver and circulating IL-6-receptor (IL-6R) forms on IL-6 bioactivity in chronic liver disease. IL-6, soluble IL-6-receptor and sgp130 levels were assayed in plasma from 45 patients with alcoholic liver disease, 84 with hepatitis C virus (HCV) infection undergoing transjugular liver biopsies and 15 healthy subjects. IL-6R mRNA was quantified on liver extracts from 54 patients with alcoholic liver disease with or without cirrhosis and 18 HCV-infected patients. The effect of gp130-Fc on fibrinogen secretion induced by IL-6 trans-signalling was evaluated on hepatocyte cultures. Levels of plasma IL-6 and sgp130, but not soluble IL-6R, increased with the stage of chronic liver disease, and correlated significantly with disease severity. Alcoholic liver disease patients had higher plasma IL-6 levels than hepatitis C, but lower liver IL-6R expression. In alcoholic and HCV-related liver diseases, liver IL-6R expression decreased with advanced fibrosis stage. In vitro, on hepatocytes, gp130-Fc blunted the acute phase response while soluble IL-6R enhanced IL-6 stimulation. In advanced chronic liver disease, high plasma IL-6 is associated with low liver IL-6R expression. This situation enables high plasma sgp130 to act as a major negative regulator of liver IL-6 trans-signalling, as demonstrated functionally here on hepatocytes. This might explain the poor acute phase response induced by IL-6 in chronic liver disease.