Interleukin (IL)-6 has anti- and pro-inflammatory functions, controlled by IL-6 classic and trans-signaling, respectively. Differences in the downstream signaling mechanism between IL-6 classic and trans-signaling have not been identified. Here, we report that IL-6 activates glycolysis to regulate the inflammatory response. IL-6 regulates glucose metabolism by forming a complex containing signal-transducing activators of transcription 3 (STAT3), hexokinase 2 (HK2), and voltage-dependent anion channel 1 (VDAC1). The IL-6 classic signaling directs glucose flux to oxidative phosphorylation (OxPhos), while IL-6 trans-signaling directs glucose flux to anaerobic glycolysis. Classic IL-6 signaling promotes STAT3 translocation into mitochondria to interact with pyruvate dehydrogenase kinase-1 (PDK1), leading to pyruvate dehydrogenase α (PDHA) dissociation from PDK1. As a result, PDHA is dephosphorylated, and STAT3 is phosphorylated at Ser727. By contrast, IL-6 trans-signaling promotes the interaction of sirtuin 2 (SIRT2) and lactate dehydrogenase A (LDHA), leading to the dissociation of STAT3 from SIRT2. As a result, LDHA is deacetylated, and STAT3 is acetylated and phosphorylated at Tyr705. IL-6 classic signaling promotes the differentiation of regulatory T cells via the PDK1/STAT3/PDHA axis, whereas IL-6 trans-signaling promotes the differentiation of Th17 cells via the SIRT2/STAT3/LDHA axis. Conclusion: IL-6 classic signaling generates anti-inflammatory functions by shifting energy metabolism to OxPhos, while IL-6 trans-signaling generates pro-inflammatory functions by shifting energy metabolism to anaerobic glycolysis.

中文翻译：

---

Interleukin-6 经典信号传导和反式信号传导利用葡萄糖代谢重编程来实现抗炎或促炎作用

白细胞介素 (IL)-6 具有抗炎和促炎功能，分别受 IL-6 经典和反式信号传导控制。IL-6 经典信号传导和反式信号传导之间下游信号传导机制的差异尚未确定。在这里，我们报道 IL-6 激活糖酵解来调节炎症反应。IL-6 通过形成含有转录信号转导激活剂 3 (STAT3)、己糖激酶 2 (HK2) 和电压依赖性阴离子通道 1 (VDAC1) 的复合物来调节葡萄糖代谢。IL-6 经典信号传导将葡萄糖流引导至氧化磷酸化 (OxPhos)，而 IL-6 反式信号传导将葡萄糖流引导至无氧糖酵解。经典的 IL-6 信号传导促进 STAT3 易位到线粒体中，与丙酮酸脱氢酶激酶 1 (PDK1) 相互作用，导致丙酮酸脱氢酶 α (PDHA) 从 PDK1 解离。结果，PDHA 去磷酸化，STAT3 在 Ser727 位点磷酸化。相比之下，IL-6 反式信号传导促进沉默调节蛋白 2 (SIRT2) 和乳酸脱氢酶 A (LDHA) 的相互作用，导致 STAT3 从 SIRT2 解离。结果，LDHA 被脱乙酰化，STAT3 在 Tyr705 处被乙酰化和磷酸化。IL-6经典信号通过PDK1/STAT3/PDHA轴促进调节性T细胞的分化，而IL-6反式信号通过SIRT2/STAT3/LDHA轴促进Th17细胞的分化。结论：IL-6经典信号传导通过将能量代谢转变为OxPhos产生抗炎功能，而IL-6反式信号传导通过将能量代谢转变为无氧糖酵解产生促炎功能。