Fasting metabolism modulates the interleukin-12/interleukin-10 cytokine axis

A crucial role of cell metabolism in immune cell differentiation and function has been recently established. Growing evidence indicates that metabolic processes impact both, innate and adaptive immunity. Since a down-stream integrator of metabolic alterations, mammalian target of rapamycin (mTOR), is responsible for controlling the balance between pro-inflammatory interleukin (IL)-12 and anti-inflammatory IL-10, we investigated the effect of upstream interference using metabolic modulators on the production of pro- and anti-inflammatory cytokines. Cytokine release and protein expression in human and murine myeloid cells was assessed after toll-like receptor (TLR)-activation and glucose-deprivation or co-treatment with 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activators. Additionally, the impact of metabolic interference was analysed in an in-vivo mouse model. Glucose-deprivation by 2-deoxy-D-glucose (2-DG) increased the production of IL-12p40 and IL-23p19 in monocytes, but dose-dependently inhibited the release of anti-inflammatory IL-10. Similar effects have been observed using pharmacological AMPK activation. Consistently, an inhibition of the tuberous sclerosis complex-mTOR pathway was observed. In line with our in vitro observations, glycolysis inhibition with 2-DG showed significantly reduced bacterial burden in a Th2-prone Listeria monocytogenes mouse infection model. In conclusion, we showed that fasting metabolism modulates the IL-12/IL-10 cytokine balance, establishing novel targets for metabolism-based immune-modulation.

近年来，细胞代谢在免疫细胞分化与功能中的关键作用已被确立。越来越多的研究证据表明，代谢过程同时调控固有免疫与适应性免疫。由于代谢改变的下游整合因子——雷帕霉素靶蛋白（mammalian target of rapamycin, mTOR）——能够调控促炎性白细胞介素（interleukin, IL）-12与抗炎性IL-10之间的平衡，本研究探讨了采用代谢调节剂进行上游干预对促炎与抗炎细胞因子生成的影响。我们在Toll样受体（toll-like receptor, TLR）活化、葡萄糖剥夺，或联合使用5'-腺苷单磷酸（AMP）活化蛋白激酶（AMPK）激活剂的条件下，对人源及鼠源髓系细胞的细胞因子释放与蛋白表达水平进行了评估。此外，我们还在小鼠体内模型中分析了代谢干预的作用效果。2-脱氧-D-葡萄糖（2-DG）介导的葡萄糖剥夺可上调单核细胞中IL-12p40与IL-23p19的表达量，但会以剂量依赖性方式抑制抗炎性IL-10的释放。采用药理学手段激活AMPK也可观察到类似的效应。与之相一致的是，我们检测到结节性硬化复合物-mTOR通路受到了抑制。与体外实验结果一致，在以Th2型免疫应答为倾向的单核细胞增生李斯特菌（Listeria monocytogenes）小鼠感染模型中，通过2-DG抑制糖酵解可显著降低体内细菌负荷。综上，本研究证实禁食状态下的代谢调控可重塑IL-12/IL-10细胞因子平衡，为基于代谢的免疫调节策略确立了全新的作用靶点。