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首页> 外文期刊>Archives of Toxicology >Metformin aggravates immune-mediated liver injury in mice
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Metformin aggravates immune-mediated liver injury in mice

机译：二甲双胍加重小鼠的免疫介导的肝损伤

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Hepatotoxicity of the antidiabetic drug metformin has been reported, but the underlying mechanisms remain unclear. We here investigated the effect of metformin in immune-mediated liver damage. While not hepatotoxic alone, metformin (200 mg/kg) aggravated concanavalin A (Con A, 12 mg/kg)-induced hepatitis, an experimental model of T cell-mediated liver injury, in both relatively resistant BALB/c and highly susceptible C57Bl/6 mice. Metformin + Con A-treated mice had elevated serum levels of pro-inflammatory cytokines TNF-alpha and IFN-gamma, accompanied by a massive mononuclear cell infiltration in the liver. This was associated with the higher numbers of CD4(+) T cells producing TNF-alpha, IFN-gamma and IL-17, CD4(+) T cells expressing chemokine receptor CXCR3 and activation marker CD27, CD4(+)CD62L(-)CCR7(-) and CD8(+)CD62L(-)CCR7(-) effector memory cells, IFN-gamma producing NK cells, IL-4 and IL-17 producing NKT cells and IL-12 producing macrophages/dendritic cells. The percentage of CD4(+)CXCR3(+)Tbet(+)IL-10(+) and CD4(+)CD69(+)CD25(-) regulatory T cells was reduced. Metformin stimulated inducible nitric oxide synthase (iNOS) expression in the liver and spleen, and genetic deletion of iNOS attenuated the hepatotoxicity of metformin. Metformin increased the autophagic light chain 3 conversion and mRNA expression of important autophagy-inducing (beclin-1, Atg5 and GABARAP) and pro-apoptotic (p21, p27, Puma, Noxa, Bax, Bad, Bak1, Bim and Apaf1), but not anti-apoptotic molecules (Bcl-xL, survivin and XIAP), which correlated with the apoptotic caspase-3/PARP cleavage in the liver. The autophagy inhibitor chloroquine (20 mg/kg) prevented liver injury and apoptotic changes induced by metformin. Therefore, metformin aggravates immune-mediated hepatitis by promoting autophagy and activation of immune cells, affecting effector, as well as liver-specific regulatory T cells and iNOS expression.
机译：已经报道了抗糖尿病药物二甲双胍的肝毒性，但其潜在机制尚不清楚。我们在这里研究了二甲双胍在免疫介导的肝损伤中的作用。二甲双胍（200 mg / kg）并非单独具有肝毒性，但在相对耐药的BALB / c和高度易感的C57B1中，加重了伴刀豆球蛋白A（Con A，12 mg / kg）引起的肝炎，这是T细胞介导的肝损伤的实验模型。 / 6只老鼠。用二甲双胍+ Con A治疗的小鼠血清中促炎性细胞因子TNF-α和IFN-γ升高，并伴随肝脏中大量单核细胞浸润。这与产生TNF-α，IFN-γ和IL-17的CD4（+）T细胞数量增加，表达趋化因子受体CXCR3和激活标记CD27，CD4（+）CD62L（-）的CD4（+）T细胞有关CCR7（-）和CD8（+）CD62L（-）CCR7（-）效应记忆细胞，产生IFN-γ的NK细胞，产生IL-4和IL-17的NKT细胞以及产生IL-12的巨噬细胞/树突状细胞。 CD4（+）CXCR3（+）Tbet（+）IL-10（+）和CD4（+）CD69（+）CD25（-）调节性T细胞的百分比降低。二甲双胍刺激肝脏和脾脏中的诱导型一氧化氮合酶（iNOS）表达，并且iNOS的基因缺失减弱了二甲双胍的肝毒性。二甲双胍增加了重要的自噬诱导（beclin-1，Atg5和GABARAP）和促凋亡（p21，p27，Puma，Noxa，Bax，Bad，Bak1，Bim和Apaf1）的自噬轻链3转化和mRNA表达。不是抗凋亡分子（Bcl-xL，survivin和XIAP），这与肝脏中凋亡的caspase-3 / PARP裂解有关。自噬抑制剂氯喹（20 mg / kg）预防了二甲双胍引起的肝损伤和凋亡变化。因此，二甲双胍通过促进免疫细胞的自噬和激活，影响效应子以及肝脏特异性调节性T细胞和iNOS表达而加重免疫介导的肝炎。

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