Molecular metabolism · 2026
Autocrine signaling may regulate exercise-induced interleukin-6 release from human skeletal muscle.
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Hvidemose Jonas Osted, Trinh Beckey, Vassilieva Alexandra, Fenger Anne-Sophie Worm, Bjerring Peter Nissen, van Hall Matthijs, Clemmesen Jens Otto, Sigurðsson Sigurður Þór, Møller Kirsten, van Hall Gerrit, Febbraio Mark A, Pedersen Bente K, Plomgaard Peter, Ellingsgaard Helga
Аннотация
BACKGROUND: Contracting skeletal muscle releases interleukin-6 (IL-6) which is primarily cleared by the liver. The tissue-specific regulation of IL-6 and soluble IL-6 receptor (sIL-6R) kinetics remains, however, poorly understood. To characterize tissue-specific IL-6 and sIL-6R exchange during exercise, we combined simultaneous arteriovenous measurements across the contracting leg, splanchnic region, and the brain with, or without, pharmacological IL-6 receptor (IL-6R) blockade.
METHODS: Thirty young, well-trained men were randomized in a double-blind, placebo-controlled design to receive either tocilizumab (IL-6R blockade) or placebo before performing moderate-intensity cycling exercise. Net tissue flux of IL-6 and sIL-6R was determined from arteriovenous concentration differences across the femoral, hepatic, and internal jugular circulation.
RESULTS: During exercise, leg IL-6 release increased with both placebo and IL-6R blockade but was significantly augmented by IL-6R blockade, suggesting a potential role for autocrine regulation of local IL-6 release. Under control conditions, the splanchnic bed was the predominant site of IL-6 clearance; however, IL-6R blockade shifted splanchnic IL-6 net balance from uptake to release. In addition, the exercising leg was identified as the source of circulating sIL-6R during exercise, whereas no consistent sIL-6R exchange occurred across the splanchnic bed or brain.
CONCLUSIONS: These findings suggest a potential role for IL-6 signaling in the autocrine regulation of IL-6 release from the contracting leg during exercise. Furthermore, exercise increases leg-derived sIL-6R, thereby contributing to increased circulating sIL-6R concentrations, while receptor-mediated splanchnic clearance appears to be a major determinant of systemic IL-6 availability during exercise in humans.
CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov (NCT06334653).
METHODS: Thirty young, well-trained men were randomized in a double-blind, placebo-controlled design to receive either tocilizumab (IL-6R blockade) or placebo before performing moderate-intensity cycling exercise. Net tissue flux of IL-6 and sIL-6R was determined from arteriovenous concentration differences across the femoral, hepatic, and internal jugular circulation.
RESULTS: During exercise, leg IL-6 release increased with both placebo and IL-6R blockade but was significantly augmented by IL-6R blockade, suggesting a potential role for autocrine regulation of local IL-6 release. Under control conditions, the splanchnic bed was the predominant site of IL-6 clearance; however, IL-6R blockade shifted splanchnic IL-6 net balance from uptake to release. In addition, the exercising leg was identified as the source of circulating sIL-6R during exercise, whereas no consistent sIL-6R exchange occurred across the splanchnic bed or brain.
CONCLUSIONS: These findings suggest a potential role for IL-6 signaling in the autocrine regulation of IL-6 release from the contracting leg during exercise. Furthermore, exercise increases leg-derived sIL-6R, thereby contributing to increased circulating sIL-6R concentrations, while receptor-mediated splanchnic clearance appears to be a major determinant of systemic IL-6 availability during exercise in humans.
CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov (NCT06334653).