Muscle-Derived IL-6 Is Not Regulated by IL-1 during Exercise. A Double Blind, Placebo-Controlled, Randomized Crossover Study

Abstract

Exercise increases muscle derived Interleukin–6 (IL–6) leading to insulin secretion via glucagon-like peptide–1. IL–1 antagonism improves glycemia and decreases systemic inflammation including IL–6 in patients with type 2 diabetes. However, it is not known whether physiological, exercise-induced muscle-derived IL–6 is also regulated by the IL–1 system. Therefore we conducted a double blind, crossover study in 17 healthy male subjects randomized to receive either the IL–1 receptor antagonist IL-1Ra (anakinra) or placebo prior to an acute treadmill exercise. Muscle activity led to a 2–3 fold increase in serum IL–6 concentrations but anakinra had no effect on this exercise-induced IL–6. Furthermore, the IL–1 responsive inflammatory markers CRP, cortisol and MCP–1 remained largely unaffected by exercise and anakinra. We conclude that the beneficial effect of muscle-induced IL–6 is not meaningfully affected by IL–1 antagonism.Trial RegistrationClinicalTrials.gov NCT01771445

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“…This is a post-hoc analysis of a randomized, placebo-controlled, double-blind, crossover, and single-center clinical study. [35] Patients were recruited and followed-up from November 2011 to May 2013 at the University Hospital Basel, Switzerland. Informed consent was obtained from all participants prior to study inclusion.…”

“…The exact study procedures were previously described. [35] Shortly, the study consisted of three visits, one screening visit in which VO 2max was determined, followed by two study visits that were separated by seven days. The VO 2max determination took place at least 7 days before the main study visits.…”

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“…Through this pathway, CRP is acting in an anti-inflammatory role by stimulating the release of IL-10 and IL-1ra, contributing to tissue repair and clearance of damaged cells, as well as resolving inflammation by inducing the anti-inflammatory M2 phenotype in macrophages, which promotes tissue repair and wound healing (Del Giudice and Gangestad, 2018). Oda et al (2002), Starkie et al (2003), Prasad (2006), Gilbert et al (2011), Rugge et al (2011), Deng et al (2012), Steensberg et al (2013), Nordmann et al (2015, and Kaiser et al (2018). Abbreviations are as follows: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; TSH, thyroid-stimulating hormone.…”

Skeletal muscle as a gene regulatory endocrine organ

“…Muscle-derived IL-6 is produced independent of TNF-a [1] and is further described to be independently regulated by IL-1 [8]. Although IL-6 is generally viewed as a proinflammatory cytokine, evidence exists that muscle-derived IL-6 has anti-inflammatory properties.…”