Definition
Interleukin-6 (IL-6) is a pleiotropic cytokine that functions as both a pro-inflammatory and anti-inflammatory mediator depending on the physiological context. PMID 37841263PMID 35969896 It is considered an exerkine (specifically a myokine) because skeletal muscle produces and releases it during physical exercise. PMID 32563931PMID 18923185
Biological function
IL-6 belongs to the four-helical cytokine family and is secreted by various cell types, including macrophages, T cells, and skeletal muscle. PMID 35969896PMID 32864098 It signals through a membrane-bound IL-6 receptor (IL-6R) that complexes with the signal-transducing glycoprotein 130 (gp130), activating intracellular JAK/STAT, MAPK, and PI3K pathways. PMID 35969896PMID 32864098 IL-6 regulates diverse biological functions including acute-phase responses, B-cell maturation, hematopoiesis, immune system coordination, metabolism, and neural development. PMID 37841263PMID 18923185PMID 33872590
Exerkine classification
The classification of IL-6 as an exerkine is supported by several key findings. During exercise, IL-6 levels can increase up to 100-fold in circulation, with the contracting skeletal muscle identified as the primary source. PMID 18923185PMID 12205025 This discovery led to the recognition of skeletal muscle as an endocrine organ capable of producing "myokines"—cytokines secreted by muscle fibers that exert autocrine, paracrine, or endocrine effects. PMID 18923185PMID 21799452 IL-6 appears to function as an energy sensor during exercise, activating hepatic glycogenolysis and adipose tissue lipolysis to meet increased metabolic demands. PMID 24655147PMID 21799452 The magnitude of IL-6 release correlates with exercise intensity, duration, and muscle glycogen depletion. PMID 24655147PMID 12205025 Studies blocking IL-6 during exercise training prevented beneficial adaptations such as reductions in visceral and epicardial fat mass, further supporting its physiological role as an exercise-induced myokine. PMID 32563931
Therapeutic potential
IL-6 represents a unique paradigm in exerkine biology: it is simultaneously the most clinically successful therapeutic target among exercise-induced myokines and a beneficial metabolic regulator during physical activity. This apparent paradox reflects IL-6's context-dependent biological roles—pathological when chronically dysregulated in disease, yet physiologically beneficial when transiently elevated during exercise. PMID 37841263PMID 35113729
Clinical Success: From Bench to Bedside
IL-6 pathway inhibition has achieved regulatory approval for multiple inflammatory conditions, establishing proof-of-concept that targeting exerkines can yield therapeutic benefit. PMID 32327746PMID 30995492 Tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, has demonstrated clinical efficacy and gained approval for rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis, Castleman disease, and cytokine release syndrome. PMID 28778870PMID 35113729PMID 32327746 Siltuximab, an anti-IL-6 ligand antibody, is approved for Castleman disease and has shown promise in oncology applications. PMID 24076269PMID 25589616PMID 35969896
These successes position IL-6 blockade as a validated therapeutic strategy, with emerging applications under investigation for neuromyelitis optica spectrum disorder, autoimmune encephalitis, COVID-19 pneumonia, and inflammatory bowel disease. PMID 37841263PMID 32327746PMID 37069261 Potential benefits in cardiometabolic diseases—including type 2 diabetes, chronic kidney disease, and cardiovascular disease—are being explored, though the benefit-risk profile in these settings requires further validation. PMID 35212585
Mechanistic Basis and Therapeutic Refinement
The therapeutic rationale centers on IL-6's role as a pleiotropic cytokine that, when chronically elevated, drives pathological inflammation through JAK/STAT pathway activation, acute-phase protein induction, and immune cell recruitment. PMID 35969896PMID 29725131 However, not all IL-6 signaling is pathological. IL-6 signals through two distinct pathways: classical signaling via membrane-bound IL-6 receptor (protective and homeostatic) and trans-signaling via soluble IL-6 receptor (predominantly pro-inflammatory). PMID 37069261PMID 29725131
This mechanistic understanding has enabled next-generation therapeutic strategies that selectively block IL-6 trans-signaling while preserving beneficial classical signaling, potentially improving the therapeutic index by maintaining homeostatic functions. PMID 37069261 Such selectivity may address current limitations, including the observation that certain inflammatory diseases do not respond to pan-IL-6 blockade and that cancer trials have yielded disappointing results despite biological rationale, likely due to tumor cell plasticity and compensatory signaling. PMID 30995492PMID 25589616
Resolving the Paradox: Context Determines Outcome
The dual nature of IL-6—detrimental in chronic inflammatory disease yet beneficial during acute exercise—highlights a fundamental principle in exerkine biology: context, magnitude, and duration of signaling determine physiological outcome. PMID 35113729PMID 37841263 During exercise, transient IL-6 elevation from contracting skeletal muscle mediates beneficial metabolic adaptations including enhanced glucose uptake, lipid oxidation, and anti-inflammatory effects, without triggering the chronic inflammatory cascade observed in disease states. PMID 32327746
This context-dependency suggests that therapeutic IL-6 inhibition for chronic inflammatory conditions does not negate the beneficial effects of exercise-induced IL-6, as the temporal dynamics, source tissue, and downstream signaling differ fundamentally between these scenarios. PMID 35113729PMID 32327746 Understanding this distinction is critical for therapeutic development and may inform strategies to selectively target pathological IL-6 signaling while preserving its physiological roles. PMID 29725131PMID 37069261
Clinical perspective: IL-6 stands alone among exerkines as having achieved regulatory approval for therapeutic applications, validating the exerkine concept while simultaneously demonstrating the complexity of translating exercise biology into pharmacological intervention. PMID 28778870PMID 30995492
Evidence
PubMed and ClinicalTrials.gov, snapshot of February 2026. Counts are keyword-based and include every study that mentions IL-6. Compare across exerkines →
References 18
Primary literature cited in this profile. Each identifier opens the article on PubMed.