目标:乙型肝炎病毒(HBV)相关肝硬化(LC),发病率和死亡率高的常见病,通常与糖尿病(DM)有关。然而,HBV相关LC期间葡萄糖调节受损的分子机制尚不清楚.
方法:分析了63例LC患者和62例LC相关DM患者的数据。采用NK细胞与胰岛β细胞共培养的方法研究葡萄糖调节机制。用LC小鼠模子验证S100A8/A9对葡萄糖的调理感化。
结果:与仅LC患者相比,LC和DM患者的外周血中出现了更高水平的源自自然杀伤(NK)细胞的干扰素(IFN)-γ和更低水平的胰岛素。源自NK细胞的IFN-γ促进β细胞坏死性凋亡和胰岛素产生受损。此外,发现LC和DM患者的S100A8/A9升高上调NK细胞中IFN-γ的产生。始终如一,在LC的小鼠模型中,用四氯化碳(CCL4)和S100A8/A9治疗的小鼠表现出血糖升高,胰岛素产生受损,IFN-γ增加,与CCL4治疗的细胞相比,β细胞坏死增加。机械上,S100A8/A9激活p38MAPK途径以增加NK细胞中IFN-γ的产生。阻断RAGE后,这些影响减弱。
结论:一起,数据表明,NK细胞产生的IFN-γ通过S100A8/A9-RAGE-p38MAPK轴诱导LC和DM患者的β细胞坏死。S100A8/A9,NK细胞水平降低,和IFN-γ对于治疗糖尿病的LC可能是有价值的。LC患者中S100A8/A9的积累可能表明DM的出现。
OBJECTIVE: Hepatitis B virus (HBV)-associated liver cirrhosis (LC), a common condition with high incidence and mortality rates, is often associated with diabetes mellitus (DM). However, the molecular mechanisms underlying impaired glucose regulation during HBV-associated LC remain unclear.
METHODS: Data from 63 patients with LC and 62 patients with LC-associated DM were analysed. Co-culture of NK cells and islet β cell lines were used to study the glucose regulation mechanism. A mouse model of LC was used to verify the effect of S100A8/A9 on the glucose regulation.
RESULTS: Higher levels of interferon (IFN)-γ derived from natural killer (NK) cells and lower levels of insulin emerged in the peripheral blood of patients with both LC and DM compared with those from patients with LC only. IFN-γ derived from NK cells facilitated β cell necroptosis and impaired insulin production. Furthermore, S100A8/A9 elevation in patients with both LC and DM was found to upregulate IFN-γ production in NK cells. Consistently, in the mouse model for LC, mice treated with carbon tetrachloride (CCL4) and S100A8/A9 exhibited increased blood glucose, impaired insulin production, increased IFN-γ, and increased β cells necroptosis compared with those treated with CCL4. Mechanistically, S100A8/A9 activated the p38 MAPK pathway to increase IFN-γ production in NK cells. These effects were diminished after blocking RAGE.
CONCLUSIONS: Together, the data indicate that IFN-γ produced by NK cells induces β cell necroptosis via the S100A8/A9-RAGE-p38 MAPK axis in patients with LC and DM. Reduced levels of S100A8/A9, NK cells, and IFN-γ could be valuable for the treatment of LC with DM. Accumulation of S100A8/A9 in patients with LC may indicate the emergence of DM.