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.

In this review, we discuss exercise as an oxidative stressor, and elucidate the mechanisms and downstream consequences of exercise-induced oxidative stress. Reactive oxygen species (ROS) are generated in the mitochondria of contracting skeletal myocytes; also, their diffusion across the myocyte membrane allows their transport to neighbouring muscle tissue and to other regions of the body. Although very intense exercise can induce oxidative damage within myocytes, the magnitudes of moderate-intensity exercise-associated increases in ROS are quite modest (~two-fold increases in intracellular and extracellular ROS concentrations during exercise), and so the effects of such increases are likely to involve redox-sensitive signalling effects rather than oxidative damage. Therefore, the responses of muscle and non-muscle cells to exercise-associated redox-sensitive signalling effects will be reviewed; for example, transcription factors such as Peroxisome Proliferator Activated Receptor-gamma (PPARγ) and Liver X-Receptor-alpha (LXRα) comprise redox-activable signalling systems, and we and others have reported exercise-associated modulation of PPARγ and/or LXRα-regulated genes in skeletal myocyte and in non-muscle cell-types such as monocyte-macrophages. Finally, the consequences of such responses in the context of management of chronic inflammatory conditions, and also their implications for the design of exercise training programmes (particularly the use of dietary antioxidants alongside exercise), will be discussed.

Background To evaluate the ability of community-based exercise programmes to facilitate public participation in exercise and hence improved cardiovascular health, we assessed the respective impacts of: a continuously monitored exercise programme based within our university (study 1); a Valleys Regional Park-facilitated community-based outdoor exercise programme (study 2); a Wales National Exercise Referral Scheme-delivered exercise-referral programme (study 3). Methods Biomolecular (monocytic PPARγ target gene expression), vascular haemodynamic (central/peripheral blood pressure, arterial stiffness), clinical (insulin sensitivity, blood lipids) and anthropometric (body mass index, waist circumference, heart rate) parameters were investigated using RT-PCR, applanation tonometry, chemical analysis and standard anthropometric techniques. Results In studies 1–3, 22/28, 32/65 and 11/14 participants adhered to their respective exercise programmes, and underwent significant increases in physical activity levels. Importantly, beneficial effects similar to those seen in our previous studies (eg, modulations in expression of monocytic PPARγ target genes, decreases in blood pressure/arterial stiffness, improvements in blood lipids/insulin sensitivity) were observed (albeit to slightly differing extents) only in participants who adhered to their respective exercise programmes. While study 1 achieved more intense exercise and more pronounced beneficial effects, significant cardiovascular risk-lowering health benefits related to biomolecular markers, blood pressure, arterial stiffness and blood lipids were achieved via community/referral-based delivery modes in studies 2 and 3. Conclusions Because cardiovascular health benefits were observed in all 3 studies, we conclude that the majority of benefits previously reported in laboratory-based studies can also be achieved in community-based/exercise-referral settings. These findings may be of use in guiding policymakers with regard to introduction and/or continued implementation of community/referral-based exercise programmes.

Objectives: Genomic markers linked to exercise-associated health benefits and/or sporting performance are increasingly used to guide decision-making in healthcare and sport/exercise science. This project investigated whether the IL-6R SNP “rs2228145” might be provisionally designated a novel physical activity/exercise marker. rs2228145 results in an Aspartate358/Alanine358 change adjacent to the site where the IL-6R protein is cleaved into two fragments, resulting in ~two-fold increases in blood-borne levels of soluble IL-6R [‘sIL-6R’].Methods: Cohorts of staff/students at Cardiff Metropolitan University donated/completed: [i] finger-prick capillary blood samples (subjected to ELISAs for sIL-6R, the associated signalling protein sgp130, and the IL-6/sIL-6R complex); [ii] cheek-swab samples containing buccal epithelial cell DNA (subjected to PCR-based IL-6R/rs2228145 genotyping assays); [iii] International Physical Activity Questionnaires (to estimate physical activity levels in the week preceding sample donation).Results: As expected, we observed significant genotype-dependent differences in blood-borne sIL-6R levels (CC (44.1±21.7ng/mL) vs. AC (28.6±7.3ng/mL) vs. AA (19.9±6.5ng/mL; P<0.05)); Importantly, AA homozygotes undertook significantly more physical activity than AC heterozygotes (6318±899 v. 3904±2280 MET-mins/week; P<0.01). Genotype was significantly associated with physical activity levels (P<0.05), and sIL-6R (P=0.197) and sgp130 (P=0.160) showed non-significant correlations with physical activity levels.Conclusions: These data suggest that IL-6R/rs2228145 genotype may influence participation in physical activity/exercise, perhaps by impacting on abilities to tolerate activity without experiencing adverse-effects. Although more research is required to confirm these preliminary findings, designation of IL-6R/rs2228145 as a novel marker, and determination of participants’ IL-6R/rs2228145 genotypes, may in future be useful tools to aid exercise-providers in designing personalised exercise programmes matched to clients/patients.

This observational study focused on the impact of Interleukin-6 (IL-6)-related factors (notably the IL-6 receptor (IL-6R) gene's rs2228145 polymorphism) on long-COVID risk in individuals who had previously experienced COVID-19 infection(s). The purpose of the study was to better understand such factors' contribution to long-COVID risk, and thus possibly initiate future strategies for using IL-6-related factors as biomarkers predictive of risk (while also obtaining data that may influence long-COVID management and treatment more generally). DNA and blood samples, plus questionnaire responses regarding long-COVID symptoms (including chronic fatigue and cognitive impairment), were collected from 175 participants who had previously experienced COVID-19 infection(s). Potential associations between self-reported long-COVID symptoms and participants' rs2228145 genotypes (determined using TaqMan-based genotyping assays) and/or their circulating IL-6, sIL-6R and sgp130 levels (determined using ELISA) were evaluated. Univariate-regression analyses demonstrated that odds of exhibiting long-COVID symptoms increased with severity/number of previous COVID-19 infection(s) and with hypertension as a co-morbidity, while vaccination decreased the likelihood of developing long-COVID. While long-COVID sufferers exhibited higher IL-6 signalling activity than healthy control individuals, rs2228145 genotype was not associated with long-COVID odds-ratios in- the entire-study cohort. Following identification of significant seasonal variations within our dataset, the entire-study cohort was stratified depending on when samples/questionnaire responses were obtained. In the resulting 'summer' sub-cohort (but not the 'winter' sub-cohort), the rs2228145 AA genotype was significantly over-represented amongst those exhibiting long-COVID symptoms, and long-COVID odds-ratios were significantly reduced for the CC and AC genotypes. While interpretation is complicated by seasonal variations, these findings may be of medical/biomedical value. Importantly, as IL-6 was higher in long-COVID sufferers than healthy controls, and rs2228145 AA genotype-bearing individuals within our 'summer' sub-cohort were at elevated risk of developing long-COVID, these findings point towards possible future use of IL-6 and/or rs2228145 genotype as biomarkers predictive of long-COVID risk, which may bring advantages regarding management and treatment of long-COVID.

Given the variability in inflammatory responses to SARS-CoV-2 infection observed within human populations, we aimed to develop an in vitro model system (based on monocyte-macrophages, a key relevant cell type) that could yield insights regarding the impact of rs2228145, a clinically relevant polymorphism within the coding region of a key inflammatory gene in the body’s response to SARS-CoV-2 infection: the interleukin-6 receptor (IL-6R) gene. Three monocyte-macrophage cell-lines (U937, THP-1, MM6) were shown to exhibit AA, AC and CC rs2228145 genotypes, respectively, and to exhibit an MM6 > THP-1 > U937 pattern regarding basal levels of soluble IL-6R (sIL-6R) release. Similar MM6 > THP-1 > U937 patterns were seen regarding the extents to which (i) circulating levels of the IL-6/sIL-6R ‘active complex’ increased and (ii) phosphorylation of the downstream transcription-factor STAT3 occurred, following treatment with SARS-CoV-2 spike protein (SP). Moreover, a blocking antibody for the ACE-2 entry receptor for SARS-CoV-2 suppressed effects (i) and (ii), suggesting that interaction between SP and ACE-2 is the initial event that triggers IL-6/IL-6R signalling in our system. Production of IL-8 occurred to greater extents in A549 lung epithelial cells treated with tissue-culture supernatants from SP-treated MM6 cultures than SP-treated THP-1 or U937 cultures. Our data indicate that the rs2228145 genotype significantly impacts upon SP-associated IL-6/sIL-6R signalling in vitro, suggesting that it may influence in vivo risk of developing severe COVID-19 and/or long-COVID symptoms following infection by SARS-CoV-2. Thus, the rs2228145 genotype may have potential as a biomarker that differentiates between patients at risk of developing severe and/or prolonged symptoms following infection by SARS-CoV-2 and those who are at less risk.