Interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) are produced by hepatic nonparenchymal cells after systemic injury and have been reported to inhibit ATP synthesis in hepatocytes, which may contribute to hepatic dysfunction in inflammatory states. To elucidate the mechanisms of action of IL-1beta and IL-6 on hepatocellular ATP synthesis, we measured the oxygen uptake rate (OUR) and mitochondrial membrane potential (MMP) of stable hepatocyte cultures, and analyzed the dynamic MMP response following the addition of mitochondrial inhibitors (antimycin A and oligomycin) with a model of mitochondrial metabolism. IL-1beta reduced mitochondrial OUR coupled to ATP synthesis via inhibition of phosphorylation reactions which dissipate the MMP, including ATP synthesis and consumption. Furthermore, the ATP synthesis rate in cytokine-free and IL-1beta-treated hepatocytes was controlled primarily by phosphorylation reactions, which corresponds to a state where the ATP synthesis rate closely follows the cellular energy demand. Thus, IL-1beta-mediated effects on electron transport and substrate oxidation reactions are not likely to significantly impact on ATP synthesis. IL-6 did not reduce mitochondrial OUR coupled to ATP synthesis, but shifted the control for ATP synthesis towards processes which generate the MMP, indicating that IL-6 induces a metabolic state where cellular functions are limited by the mitochondrial energy supply.

中文翻译：

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完整肝细胞线粒体代谢的对照分析：白介素-1β和白介素-6的作用。

白细胞介素-1β（IL-1beta）和白细胞介素-6（IL-6）由系统性损伤后的肝脏非实质细胞产生，据报道抑制肝细胞中的ATP合成，在炎性状态下可能导致肝功能障碍。为了阐明IL-1β和IL-6对肝细胞ATP合成的作用机理，我们测量了稳定肝细胞培养物的摄氧率（OUR）和线粒体膜电位（MMP），并分析了添加MMP后的动态MMP反应。具有线粒体代谢模型的线粒体抑制剂（抗霉素A和寡霉素）。IL-1β通过抑制耗散MMP的磷酸化反应（包括ATP的合成和消耗），减少了与ATP合成偶联的线粒体OUR。此外，在无细胞因子和经IL-1β处理的肝细胞中，ATP合成速率主要受磷酸化反应控制，这与ATP合成速率紧随细胞能量需求的状态相对应。因此，IL-1β介导的对电子传输和底物氧化反应的影响不太可能对ATP合成产生显着影响。IL-6不会减少与ATP合成相关的线粒体OUR，但会将ATP合成的控制转移到生成MMP的过程，这表明IL-6诱导了一种代谢状态，其中细胞功能受到线粒体能量供应的限制。IL-1beta介导的对电子传输和底物氧化反应的影响不太可能对ATP合成产生显着影响。IL-6不会减少与ATP合成相关的线粒体OUR，但会将ATP合成的控制转移到生成MMP的过程，这表明IL-6诱导了一种代谢状态，其中细胞功能受到线粒体能量供应的限制。IL-1beta介导的对电子传输和底物氧化反应的影响不太可能对ATP合成产生显着影响。IL-6不会减少与ATP合成相关的线粒体OUR，但会将ATP合成的控制转移到生成MMP的过程，这表明IL-6诱导了一种代谢状态，其中细胞功能受到线粒体能量供应的限制。