Interleukin-6 classic and trans-signaling utilize glucose metabolism reprogramming to achieve anti- or pro-inflammatory effects

Metabolism. 2024 Jun:155:155832. doi: 10.1016/j.metabol.2024.155832. Epub 2024 Mar 2.


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.

Keywords: Glucose metabolism; Inflammatory functions; Interleukin-6.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Glucose* / metabolism
  • Glycolysis / physiology
  • Hexokinase / metabolism
  • Humans
  • Inflammation / metabolism
  • Interleukin-6* / metabolism
  • Metabolic Reprogramming
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Phosphorylation
  • Phosphorylation
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase* / metabolism
  • STAT3 Transcription Factor* / metabolism
  • Signal Transduction* / physiology


  • Interleukin-6
  • Glucose
  • STAT3 Transcription Factor
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Hexokinase