Physical exercise is the best therapy in reducing interleukin-6 levels as an inflammatory mediator: a systematic review

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Introduction

Aging in humans is a natural physiological mechanism that occurs due to the buildup of cellular damage brought on by different stimuli which results in the decline of physical functions and organ systems [20]. The occurrence of aging in humans can trigger various diseases such as diabetes mellitus, Alzheimer’s disease, disorders of the cardiovascular system, Parkinson’s disease, long-term obstructive lung disease, and can even increase the occurrence of osteoporosis [10, 19, 21, 59]. The occurrence of inflammatory processes that are still within standard limits in the human body is indeed a natural physiological factor that triggers aging [51]. If the body is able to carry out the adaptation process properly, it will result in repair and maintenance, thereby increasing the degree of human health [46]. Based on epidemiological data, the following factors contribute significantly to slowing down the aging process, such as maintaining a regular diet, regular physical activity, and eating plenty of nutritious foods [24].

The change in lifestyle from a healthy lifestyle to an unhealthy lifestyle is a major problem found throughout the world that triggers an increase in non-communicable diseases [2]. Chronic age-related diseases are triggered by various factors including changes in the immune system, metabolic responses, stress responses and imbalances caused by inflammation [3]. Exercise is the best physical therapy in inhibiting cellular aging through reducing inflammation levels, and regulating immune function [43]. The immune system, cardiovascular system, metabolic system, and neurological system all experience significant therapeutic effects from exercise, all of which contribute to an increase in human health [9].

One non-pharmacological treatment that scientific research has shown contributes to reducing inflammation, regulating the immune system, and delaying cellular aging [43]. Exercise has a systemic effect on organs and tissues by releasing chemicals called myokines [9]. Among these is IL-6, which influences advantageous physiological and metabolic alterations in the liver, bone, skeletal muscle, white adipose tissue, immune cells, and neurological system [17]. Exercise, as we all know, has anti-inflammatory properties that can modulate immunological dysfunction and other complications, as well as reducing inflammation, improving insulin sensitivity, and regulating energy expenditure [32]. Another aspect of exercise is that significant physiological changes affect the immune system, triggering hormonal and immunological responses [12].

IL-6 needs to be understood that it has a number of hematologic and metabolic ramifications in addition to both pro- and anti-inflammatory actions [43]. These systemic effects illustrate that the mechanisms of exercise-induced signal transduction in cellular responses are complex and intricate [14]. A key modulator of the acute and chronic phases of inflammatory activity, IL-6 is also linked to particular cellular and hormone immunological responses, including T cell activation, immunoglobulin production, and late-stage B cell differentiation [43]. Neutrophilic leukocyte infiltrations can be transformed into many lymphocyte infiltrations by the interleukin-6 receptor (IL-6R), which raises IL-6 levels in a number of inflammatory illnesses [5].

We know that physical exercise causes complex physiological reactions, especially related to the inflammatory response. Numerous routes involved in signal transduction are still confusing in the stages of the inflammatory response. In addition, the effects of the type, duration and intensity of exercise also have an impact on the mechanism of IL-6 increase. The stages of the inflammatory response are very important to understand to provide clarity regarding the pathways and mechanisms generated during exercise. The positive and negative effects of inflammation during exercise need to be known, especially the signal transduction mechanisms and their implications. Meanwhile, from various existing reviews, it is still minimal and has not been explained with certainty regarding the stages and mechanisms of exercise in increasing the inflammatory response through an increase in IL-6. Therefore, in this review, researchers want to explore in depth how the effect of physical exercise and the underlying mechanism in increasing IL-6 levels as an inflammatory response to exercise.

Materials and methods

Study Design

For this type of systematic review investigation, journal databases such as Science Direct, Web of Science, MEDLINE-Pubmed, and Scopus are searched. These platforms are regarded as the best in the world since they compile papers having a solid scientific foundation and impact.

Eligibility criteria

The inclusion criteria for the study were developed by looking at papers that addressed IL-6, inflammation, and exercise that were released within the previous five years. Furthermore, our analysis did not include journals that did not meet the standards for scientific validity or those were not included in trustworthy search indexes like Scopus, Web of Science, Pubmed, or Science Direct.

Procedure

Full manuscripts, abstracts, and paper titles were added to the Mendeley database after being verified and checked. In the first stage, 126 publications were found using Science Direct, Pubmed, and Web of Science databases. For the second screening stage, 85 papers that met the abstract and title requirements were selected. Requests for additional processing were submitted for 48 items in the third stage. At this point, we organized the items based on their overall suitability. Ten papers that met the inclusion criteria were selected for analysis after a thorough review and observation process. The operational criteria in this investigation were to comply with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) evaluation.

 

Figure 1. PRISMA flowchart of the article selection process

 

Table 1. Summary of the design and intervention of the studies

Author	Design	Participants	Participants age	Intervention	Outcome
K. Makiel et al., 2023 [32]	Randomized controlled trial	62 male with metabolic syndrom	30-45 years	Aerobic Exercise Use the treadmill to warm up for five minutes. Aerobic exercise of brisk walking and jogging. Exercise was performed at 70% HR Max. Duration of exercise per session for 45 minutes. Total training was conducted for 12 weeks Combined Aerobic Resistance Exercise Warm up for 5 minutes of walking on the treadmil. Full body workout consisting of squats, push ups, one-arm dumbbell row. Exercise intensity was gradually increased each week. After resistance training, participants followed aerobic exercise on a treadmill with an intensity of HR Max 70%	Following 12 weeks of training, IL-6 levels significantly decreased in the group receiving physical exercise intervention. However, there was no discernible decline in the control group
V. Soares et al., 2020 [48]	Randomized controlled trial	25 athletes	44 years	Aerobic Exercise The sample spent three hours and ten minutes walking 28.2 kilometers. The activity was carried out for 4 days to compare between pre, day one, day two, day three, and day four IL-6 levels	It is known that on the first day, IL-6 concentration increased significantly. On the other hand, the trend of IL-6 concentration significantly decreased on the second, third, and fourth days
T. Goj et al., 2023 [17]	Randomized controlled trial	22 individuals	30 years	Endurance Exercise The participants performed acute exercise using an ergometer for 30 minutes with an exercise intensity of 80% VO2 Max. After completing the first acute exercise, participants underwent 8 weeks of supervised endurance training at 80% VO2 Max. The exercise consisted of walking on a treadmill for 30 minutes and ergocycle exercise for 30 minutes.	IL-6 levels are acutely elevated. There is no significant difference between pre 8 weeks and post 8 weeks.
P.W. Chen et al., 2022 [8]	Randomized controlled trial	11 male collegiate swimmers	21 years	Resistance Exercise After the participants perform dynamic stretching, they perform core exercises including squats, deadlifts, and bench presses. Each exercise includes 6 sets of 10 reps at 75% of maximum reps. Rest lasts 2 minutes between sets	The study’s findings demonstrated that IL-6 levels significantly increased right after physical activity. However, there was a downward trend 24 hours after physical exercise. And finally at 48 hours after physical exercise IL-6 levels tend to stabilize
S. Proschinger et al., 2023 [40]	Randomized controlled trial	24 recreationally active runners	29 years	Best line testing is done to determine the maximum capacity of the sample. So the sample is tested running using a treadmill until it experiences fatigue. After that the sample did 2 types of tests starting from HIIT and MCE whose details are as follows. High Intensity Interval Training Warm-up is done for 7 minutes at 70% VO2 Max running speed. Followed by 6 intervals of running for 3 minutes at a speed of 90% VO2 Max. These intervals are followed by 3 minutes of active recovery at a pace equivalent to 50% VO2 Max Moderate Continuous Exercise The session started at 50% VO2 Max and was constant throughout the 50-minute intervention period. The exercise ends with a cool down	In both groups, IL-6 levels rose right after physical activity. But after 1 hour there was a decrease in IL-6 levels
B. Chaki et al., 2024 [6]	Randomized controlled trial	64 sedentary	10-15 years	Aerobic Training The subject warms up running on a treadmill. Subjects continue to run until a certain slope until they experience fatigue	There was a significant increase in IL-6 concentration after physical exercise intervention
P. Villar-Fincheira et al., 2021 [55]	Randomized controlled trial	44 male marathon runners	37 years	Low Training 1. Athletes in this group performed pre-training 16 weeks prior to the marathon. 2. The training load consisted of less than 100 km per week High Training Athletes in this group performed pre-training 16 weeks prior to the marathon. The training load consisted of more than 100 km per week	There was a significant increase in IL-6 levels in the group with physical exercise interventions both low and high immediately after running a marathon
M.N. Amin et al., 2021 [1]	Randomized controlled trial	18 Egyptian male handball players	21 years	Handball Training Handball training with an intensity of 60% – 70% of VO2 Max. Training consists of jogging, passing the ball while standing, or while jogging and kicking the ball for 1.5 hours	There was a significant decrease in IL-6 levels 5 minutes after the physical exercise intervention
M. Kooti et al., 2022 [27]	Randomized controlled trial	24 obese women	20-35 years	Endurance Resistance Training The subject began by performing resistance exercises, which included seated rowing, leg press, leg curl, leg extension, and bench press. Each resistance exercise was done 8-12 times at a 75% repetition maximum (1RM), with a one-minute rest in between sets. Each session of the resistance training program included 15 minutes of jogging or walking at 60% of the reserve heart rate. For 12 weeks of the intervention, exercise was done three times a week	There was a significant reduction in IL-6 levels after 12 weeks of physical exercise intervention
H. Islam et al., 2024 [22]	Randomized controlled trial	active adults	30 years	Moderate Continuous Exercise Exercise on an ergometer at 70% VO2 Max intensity. Exercise is performed continuously Heavy Continous Exercise Exercise on an ergometer with 70% VO2 Max intensity or 10% difference from moderate continuous exercise. Exercise is performed continuously Heavy Interval Exercise Exercise on the ergometer at maximal intensity with 1 minute of rest and 1 minute of exercise	In all three groups with various types of physical exercise intensity, it was proven that immediately after exercise, IL-6 levels increased. The peak increase occurred at 30 minutes after the physical exercise intervention. After experiencing an increase at 30 minutes after exercise. At the 90th minute after physical exercise IL-6 levels decreased

 

Results and discussion

The aim of this comprehensive review is to determine how physical activity affects IL-6 levels as an intermediary of the process of inflammation. Based on the research data that has been analyzed, it is proven that chronic physical exercise can reduce inflammation levels by reducing IL-6 levels. The findings of experimental studies carried out by K. Makiel et al., 2023 proved that physical exercise both aerobic exercise and combined resistance exercise for 12 weeks can reduce IL-6 levels [32]. The results also compared between aerobic and combined aerobic resistance exercise interventions. In the group with aerobic exercise intervention at week one and week 6 IL-6 levels increased. After week 6 IL-6 levels experienced a downward trend until week 12 of intervention. In the group, there is a mix of aerobic resistance exercise starting week 1 IL-6 levels increased. However, there was a downward trend in IL-6 levels until week 12 of the intervention. 4 weeks after the last intervention IL-6 levels remained significantly decreased.

In other research from V. Soares et al., 2020 showed that aerobic exercise performed for 4 consecutive days compared with pre-intervention data showed that on the first day IL-6 levels increased significantly, However, IL-6 levels gradually and significantly decreased on the second to last day on day 4 [48]. The findings of earlier studies carried out by P.W. Chen et al., 2022 proved that resistance training intervention after physical exercise for a moment IL-6 levels increased significantly, then IL-6 levels decreased significantly at 24 hours after physical exercise intervention and there was no significant difference at 48 hours after physical exercise [8]. So, it can be concluded from these data that 24 hours after physical exercise intervention is the peak phase of the decline in IL-6 levels, but further research must be done to confirm it. In his research S. Proschinger et al., 2023 demonstrated that exercise, including both moderate-intensity continuous exercise and high-intensity interval exercise, had a negative effect on IL-6 levels an hour later but a beneficial effect in the short term when compared to the pretest [40].

The increase in IL-6 after physical exercise intervention is a physiological response caused as a mediator of inflammation. According to the findings of the study carried out by B. Chaki et al., 2024 proved that aerobic training is proven to provide an rise in IL-6 concentrations [6]. In addition, the data is also reinforced by a review from P. Villar-Fincheira et al., 2021 that there was a significant increase in IL-6 levels in subjects who had run a marathon [56]. The results of another study on handball athletes proved that IL-6 levels decreased significantly 5 minutes after the handball training intervention [1]. Other data on the results of research conducted by M. Kooti et al., 2022 It has been proven that endurance resistance traning intervention for 12 weeks has an effect on significantly reducing IL-6 levels [27]. So that from several research results prove that chronic physical exercise is indeed proven effective in reducing IL-6 levels.

Effects of physical exercise on inflammatory response and oxidative stress

It has been demonstrated that aerobic exercise increases oxidative stress and reactive oxygen species (ROS) [47]. Increased accumulation of ROS during exercise will promote redox disturbances that result in oxidative damage to cellular components (J. Kruk et al., 2019) [28]. During physical exercise, especially resistance training, it will trigger responses from several human organs including the musculoskeletal, immunological, respiratory, cardiovascular, and endocrine systems [33]. Exercise provides the body’s response to maintain a state of homeostasis including regulators in the endocrine system and cytokine system specific responses [54]. During physical exercise, 5 interrelated phases of cellular and molecular events occur, namely the degeneration-necrosis phase, the phases of maturation/remodeling, immunological response, regeneration, and functional recovery, which are interconnected with each other [15].

The occurrence of oxidative damage also impacts and triggers the aging process and decreases some body functions [52]. Exercise-induced ROS are key in the adverse effects caused by oxidative stress [4]. Acutely, Inflammation helps to restore tissue homeostasis and is a natural biological reaction to tissue injury. Mechanical stress brought on by exercise also encourages the release of hormones like cortisol and catecholamines, which in turn triggers the creation of other cytokines like IL-6. Furthermore, stress’s effects cause the immune system to be suppressed [26]. At inflammatory locations, macrophages, fibroblasts, and endothelial cells produce IL-6, which regulates the degree of the inflammatory response in tissues [37]. IL-6 levels were significantly elevated during acute physical exercise [55]. But this is a physiological reaction to physical activity.

Mechanism of chronic exercise on IL-6 level decrease

Regular exercise has a major effect in enhancing physical wellness. Exercise usually refers to a programmed and routine plan for optimal benefits [30]. Physical exercise serves as a preventative measure against a wide range of diseases and has the ability to result in positive treatment outcomes for illnesses [57]. Interleukins are a class of proteins that attach to particular receptors and communicate with leukocytes. Monocytes, macrophages, CD4⁺ helper T cells, and endothelial cells are the primary producers of ILs [13]. A crucial pleiotropic cytokine, IL-6 regulates the body’s immune response to infection, damage, or inflammation by inducing and coordinating different response components in the acute phase [34].

Studies have demonstrated that during physical activity, skeletal muscle releases myokines like IL-6 [32]. Glycogen levels, as well as the length and intensity of physical activity, are associated with the generation of IL-6. The amount of glycogen, as well as the length and intensity of physical exercise, determines the amount of IL-6 produced [35]. One indicator of the inflammatory response is IL-6. Chronic disorders associated with aging will arise when IL-6 levels rise as a result of a number of causes, such as stressful situations, immune changes, metabolic stress responses, and imbalances between free radicals and antioxidants [45]. The sympathetic nervous system is activated when we engage in intense physical activity [25]. Additionally, exercise boosts the heart’s function, which in turn increases the body’s ability to absorb oxygen [58]. Very intricate processes involving molecular mechanisms take place in skeletal muscle.

Skeletal muscle releases IL-6 into the interstitium and systemic circulation system during physical activity. IL-6 also functions in endocrine, autocrine, and paracrine ways to redirect energy to the contracting muscle [37]. Plasma IL-6 concentration levels rise during physical activity and reach their maximum at the conclusion of the workout [37, 38]. Exercise that involved greater muscle groups, lasted longer, and was more intense increased circulating IL-6 the most [37]. After exercise, muscle-derived IL-6 is quickly removed from plasma due to accelerated hepatic clearance and the cessation of skeletal muscle contraction. It has a half-life of five minutes [53].

Since it has been demonstrated that regular exercise lowers IL-6 levels, the ultimate rise in plasma IL-6 levels serves as a gauge of each person’s level of fitness and exercise adaptation [42]. Individuals who routinely exercise have lower basal IL-6 levels than those who exercise seldom since the reduction in IL-6 levels found after only one exercise session was also apparent in basal subjects [18]. Resistance training has also been demonstrated in other research to lower skeletal muscle IL-6 mRNA, which subsequently creates an exercise-induced adaption mechanism [56].

Increased IL-6 secretion is caused by Ca²⁺ ions escaping from skeletal muscle. In particular, during skeletal muscle contraction, Ca²⁺ ions in the sarcoplasmic reticulum release the cytoplasm of skeletal muscle cells [36]. Regular exercise also promotes an increase in anti-inflammatory cytokines, and it has been demonstrated that exercise improves insulin sensitivity, and frequent exercise also caused a decrease in visceral fat [11, 41]. By suppressing the production of the proinflammatory cytokine TNFα and causing the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist (IL-1RA) to enter the bloodstream, physiologic concentrations of IL-6 can replicate the anti-inflammatory effects of exercise sessions in humans [37]. By directly affecting the adrenal marrow, IL-6 infusion also promotes the production of cortisol, a potent anti-inflammatory hormone, into the bloodstream [23]. It causes the pituitary gland to release the adrenocorticotropic hormone, so simulating how exercise affects the hypothalamic-pituitary-adrenal axis. In contrast to the M1 (pro-inflammatory) phenotype, IL-6 encourages macrophage polarization toward the M2 (anti-inflammatory) phenotype [7, 37].

Acute physical activity has been demonstrated to raise IL-6, which affects the anti-inflammatory milieu, but exercise also raises insulin sensitivity. AMPK and p38 MAPK activation, as well as the buildup of Ca²⁺, lactate, and ROS, are examples of energetic stress signals that occur during intense exercise, causes skeletal muscle to release IL-6, which happens when TNFα/IL-1β production and NF-κB signaling are not present, and when the anti-inflammatory cytokines IL-10 and IL-1RA are present ^[29, 49, 50]. On the other hand, IL-6 produced by inflammatory cells such cancer cells, stromal cells, and macrophages is closely linked to NF-κB signaling upstream and happens at the same time as TNFα production [31]. Therefore, IL-6 signaling takes place in a milieu rich in growth factors, genetic instability, DNA damaging agents, and activated stroma when IL-6 release is prompted by upstream inflammatory signals. Although IL-6/STAT3 signaling by itself does not cause cancer, prolonged STAT3 activation in an inflammatory and DNA-damaged environment can encourage the development and spread of malignant transformation [37]. The majority of research to far has demonstrated that different forms of acute exercise raise plasma IL-6 levels [39]. This rise happens exponentially, reaching a peak at the end of the workout that is typically 100 times the baseline levels and rapidly returning to pre-exercise levels [44].

Strenght and limitations

The advantage of this systematic review is that it only looked at randomized controlled trials, which is the most reliable type of scientific evidence as there is no possibility of an ambiguous causal relationship. In addition, the samples taken were focused on humans so that all samples could show homogeneous data and not be mixed with other categories like samples using animals.

The limitation that we encountered was the lack of discussion and discussion related to how physical exercise in increasing IL-6 and how the mechanism underlying the decrease in IL-6 levels after chronic exercise is still minimal discussion. Therefore, this review is deemed important to do in order to add insight and repertoire of science related to how the mechanisms underlying physical exercise acutely in increasing IL-6 and chronically can provide a decrease in IL-6 levels.

Conclusions

Based on the related articles we found, it can be said that regular, chronic physical activity has been shown to reduce IL-6 levels as a marker of inflammation after exercise. Regular physical exercise is highly recommended as the best therapy in improving body health through reducing IL-6 levels as one of the biomarkers of inflammation.

About the authors

Novadri Ayubi

Universitas Negeri Surabaya

Author for correspondence.
Email: novadriayubi@unesa.ac.id
ORCID iD: 0000-0002-5196-6636

S.Or., M.Kes., Dr.

Indonesia, Surabaya

Junian Cahyanto Wibawa

STKIP PGRI Trenggalek

Email: juniancahyanto96@stkippgritrenggalek.ac.id
ORCID iD: 0000-0002-4667-5981

S.Or., M.Kes., Master

Indonesia, Trenggalek

Joseph Lobo

Bulacan State University

Email: joseph.lobo@bulsu.edu.ph
ORCID iD: 0000-0002-2553-467X

Ph.D

Philippines, Malolos

Anton Komaini

Universitas Negeri Padang

Email: antonkomaini@fik.unp.ac.id
ORCID iD: 0000-0002-2955-0175

S.Si., M.Pd., Professor

Indonesia, Padang

Cyuzuzo Callixte

University of Rwanda

Email: c.cyuzuzo@ur.ac.rw
ORCID iD: 0000-0002-9137-5515

M.Sc.

Rwanda, Butare

Ainun Zulfikar Rizki

Universitas Negeri Surabaya

Email: ainun.20015@mhs.unesa.ac.id
ORCID iD: 0000-0003-0249-4908

S.Pd., M.Pd.

Indonesia, Surabaya

Alvin Afandi

Universitas Negeri Surabaya

Email: alvinafandi09@gmail.com
ORCID iD: 0009-0009-7161-3852
Scopus Author ID: 59538274900

S.Pd., M.Pd.

Indonesia, Surabaya

Muhamad Ichsan Sabillah

Universitas Negeri Surabaya

Email: muhamadsabillah@unesa.ac.id
ORCID iD: 0000-0001-6081-8590

S.Or., M.Or., Dr.

Indonesia, Surabaya

References

Supplementary files