CoChat
Sign Up
Cited by 182Exercise and Physiological ResponsesCytokine Signaling Pathways and InteractionsCardiovascular and exercise physiology

IL‐6 signaling in acute exercise and chronic training: Potential consequences for health and athletic performance

Open access
Nash, Dan, Hughes, Michael G., Butcher, Lee, Aicheler, Rebecca, Smith, Paul, Cullen, Tom, Webb, Richard·2023·Scandinavian Journal of Medicine & Science in Sports
DOI 10.1111/sms.14241PMC PMC10092579
Open this paper in CoChat — free accountOpen PDF

Abstract

The cytokine interleukin-6 (IL-6) is involved in a diverse set of physiological processes. Traditionally, IL-6 has been thought of in terms of its inflammatory actions during the acute phase response and in chronic conditions such as rheumatoid arthritis and obesity. However, IL-6 is also an important signaling molecule during exercise, being acutely released from working muscle fibers with increased exercise duration, intensity, and muscle glycogen depletion. In this context, IL-6 enables muscle-organ crosstalk, facilitating a coordinated response to help maintain muscle energy homeostasis, while also having anti-inflammatory actions. The range of actions of IL-6 can be explained by its dichotomous signaling pathways. Classical signaling involves IL-6 binding to a cell-surface receptor (mbIL-6R; present on only a small number of cell types) and is the predominant signaling mechanism during exercise. Trans-signaling involves IL-6 binding to a soluble version of its receptor (sIL-6R), with the resulting complex having a much greater half-life and the ability to signal in all cell types. Trans-signaling drives the inflammatory actions of IL-6 and is the predominant pathway in disease. A single nucleotide polymorphism (rs2228145) on the IL-6R gene can modify the classical/trans-signaling balance through increasing the levels of sIL-6R. This SNP has clinical significance, having been linked to inflammatory conditions such as rheumatoid arthritis and type 1 diabetes, as well as to the severity of symptoms experienced with COVID-19. This review will describe how acute exercise, chronic training and the rs2228145 SNP can modify the IL-6 signaling pathway and the consequent implications for health and athletic performance.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1111/sms.14241

Cites

139 of 139 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Under pathological conditions such as atherosclerosis, IL-6 trans-signaling mediated by soluble IL-6 receptors predominates, promoting vascular inflammation, monocyte recruitment, and plaque instability.

    “Under pathological conditions like atherosclerosis, the “trans-signaling” pathway mediated by soluble IL-6 receptors predominates, promoting vascular inflammation, monocyte recruitment, and plaque instability [14,36].”

    From Exercise-Induced Myokines in Obesity-Related Metabolic Disorders and Cardiovascular Protection: A Narrative Review (2026) · cites this paper as [14]

    The Introduction describes trans-signaling through soluble IL-6 receptors as pro-inflammatory and says it promotes leukocyte infiltration; the paper also describes trans-signaling as predominant in disease. Its atherosclerosis entry in Table 1 reports circulating marker concentrations, but the copy does not establish that trans-signaling predominates specifically in atherosclerosis or that it causes monocyte recruitment and plaque instability. Page numbers were not available in the indexed copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • HIIT produces dramatic energy fluctuations and hypoxic stimuli that elicit a rapid, high-amplitude IL-6 peak; this IL-6 acts through the classical receptor to initiate transcription of anti-inflammatory cytokines IL-10 and IL-1Ra.

    “HIIT combines intense metabolic perturbation with intermittent recovery, producing dramatic energy fluctuations and hypoxic stimuli that elicit a rapid, high-amplitude IL-6 peak. This IL-6 signal acts through the classical receptor (not trans-signaling) to initiate transcription of anti-inflammatory cytokines (IL-10, IL-1Ra) [14].”

    From Exercise-Induced Myokines in Obesity-Related Metabolic Disorders and Cardiovascular Protection: A Narrative Review (2026) · cites this paper as [14]

    In “Endocrine actions of IL-6 during exercise” (page unavailable), the paper says an early exercise-associated IL-6 peak induces later IL-10 and IL-1Ra peaks, likely through classical receptor signaling. It does not establish that HIIT’s intermittent recovery or hypoxic stimuli produce a rapid, high-amplitude peak, or specifically demonstrate transcription of those cytokines. The claim also states the proposed signaling mechanism more definitively than the paper does. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The intense metabolic stress induced by HIIT triggers a pulsatile IL-6 release that activates anti-inflammatory cascades, while Metrnl upregulation has been associated with improved cardiac function in human studies.

    “The intense metabolic stress induced by HIIT triggers a pulsatile IL-6 release that activates anti-inflammatory cascades [14,34], while Metrnl upregulation has been associated with improved cardiac function in human studies [66].”

    From Exercise-Induced Myokines in Obesity-Related Metabolic Disorders and Cardiovascular Protection: A Narrative Review (2026) · cites this paper as [14]

    The Introduction’s ‘IL-6 and exercise intensity’ section reports greater IL-6 increases with higher-intensity exercise, and ‘Endocrine actions of IL-6 during exercise’ describes an initial exercise-associated IL-6 peak followed by anti-inflammatory signaling. The paper does not establish that HIIT specifically produces pulsatile IL-6 release through metabolic stress; it says the molecular mechanism of IL-6 production remains unclear. The Metrnl clause is attached to a different citation and is not judged here. Page numbers were not available in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • IL-6 release during a 30 min walk at 50% VO2 max in sedentary middle-aged men is minimal, whereas prolonged physical activity such as 5 h at 40% VO2 max leads to a 19-fold increase in IL-6 levels.

    “Studies have shown that IL-6 release during a 30 min walk at 50% VO2 max in sedentary middle-aged men is minimal, whereas prolonged physical activity, such as 5 h at 40% VO2 max leads to a 19-fold increase in IL-6 levels [42,43,44].”

    From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [44]

  • Circulating sIL-6R concentrations increase acutely during an exercise bout.

    “Circulating sIL-6R concentrations also increase acutely during an exercise bout [ 52 , 53 ]”

    From IL-6 Activity is Required for Maximal Catecholamine Release During High-Intensity Exercise in Men (2026) · cites this paper as [52]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Nash, D., Hughes, M. G., Butcher, L., Aicheler, R., Smith, P., Cullen, T., & Webb, R.
Affiliations
  • Cardiff Metropolitan University (GB)
  • Coventry University (GB)
Corresponding author
Webb, Richard
ORCID
Venue
Scandinavian Journal of Medicine & Science in Sports
Publisher
Wiley
Published
2022-10-08
Volume
33
Issue
1
Pages
4-19
ISSN
  • 0905-7188 (ISSN-L)
  • 1600-0838
DOI
10.1111/sms.14241
PMC
PMC10092579
OpenAlex
W4297461708
Cited by
182
References
139
Citations by year
2026: 72 · 2025: 63 · 2024: 39 · 2023: 7 · 2022: 1
FWCI
3.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Scandinavian Journal of Medicine and Science in Sports (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Repository@Hull (Worktribe) (University of Hull) (publishedVersion, other-oa)
  • Pure (Coventry University) (publishedVersion, cc-by-nc-nd)
  • Repository@Hull (Worktribe) (University of Hull) (submittedVersion, cc-by-nc-nd)
  • Figshare (submittedVersion, cc-by-nc-nd)
Funders
European Social Fund
Topics
  • Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
Keywords
interleukin-6, IL-6 signaling, acute exercise, trans-signaling, soluble IL-6 receptor, anti-inflammatory activity, acute phase response, athletic performance, COVID-19 severity, rheumatoid arthritis, type 1 diabetes
MeSH terms
COVID-19, Arthritis, Rheumatoid, Humans, Exercise, Interleukin-6, Athletic Performance

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review