As I mentioned in Part 1 of this two-part post, inflammation is a two-edged sword, requiring a fine balance between initiation and termination, in order to promote health and not disease.
With this idea in mind, I came across a recent review article by Gleeson et al. in Nature Reviews Immunology, which focuses on the anti-inflammatory effects of exercise and its implications in health and disease.1
The authors observed that pathogenesis of various conditions associated with many metabolic and other diseases (such as diabetes, cardiovascular disease, certain cancers, dementia and so forth) have been shown to be dependent on the interplay of metabolic and immune processes, and appear to be associated with inflammation. Exercise, or high physical activity, is known to protect against the development of many of these conditions, and therefore, may have anti-inflammatory properties. The authors reviewed the existing literature to seek the evidence for that hypothesis.
The authors compiled a list of several possible mechanisms by which exercise exerts its anti-inflammatory effect. This includes:
- A reduction in visceral fat mass – this exerts an indirect effect to decrease inflammation, since accumulation of fat in the omentum, liver and muscles, as well as the expansion of adipose tissue, results in enhanced production of certain inflammatory mediators (such as TNF, Leptin, IL6, CCL2/MCP1, CCL5/RANTES etc.) and consequent reduction of anti-inflammatory cytokines (such as Adiponectin). An obese body lives in a persistent state of low-grade systemic inflammation, and therefore, fat-loss through exercise has an anti-inflammatory effect.
- Release of IL6 from working muscles – A fall in muscle glycogen content with exercise signals the muscles to secrete IL6, keeping the concentration of this pro-inflammatory cytokine high for the duration of the exercise. This rise in circulating IL6 appears to start off a cascade in which certain anti-inflammatory cytokines (IL10, IL-1RA) are elevated and exert their direct and indirect effects to minimize inflammation induced tissue damage. However, elevation of IL6 is dependent upon the duration of activity, and a significant increase requires 2 and a half hour of more of strenuous exercise.
- Increased levels of circulating cortisol and adrenaline – IL6 stimulates the release of the stress hormone, cortisol, from adrenal glands. Besides, exercise itself activates the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, thereby signaling the production of more cortisol and adrenaline from the adrenal gland, as well as adrenaline/noradrenaline from the adrenal medulla, for the duration of the exercise. Cortisol and the catecholamines (adrenaline and noradrenaline) are both known to have potent anti-inflammatory effects.
The authors also discussed a few other possibilities that don’t have enough evidence yet – such as exercise may (a) reduce the influx of macrophages (histiocytic inflammation) into adipose tissue, (b) prevent the adhesion of inflammatory cell to the inner wall (endothelium) of blood vessels, by reducing the expression of a surface molecule called ICAM-1, © attenuate the number of pro-inflammatory mononuclear leukocytes (monocytes) in the total blood pool; and so forth.
What first caught my attention was the authors’ surmise that exercise could reduce (downregulate) the surface expression of a set of receptor molecules (the TLRs) that are very important in the detection of and host response to microbial pathogens. Blood monocytes from physically active individuals had decreased TLR4 expression, and following an acute, prolonged bout of strenuous exercise, the expression of TLR1, TLR2 and TLR4 on monocytes was decreased for at least several hours. The reduction in TLR expression has been associated with decreased inflammatory cytokine production.
But this doesn’t augur well, since TLR1, TLR2 and TLR4 represent major mechanisms by which immune cells detect bacterial and fungal pathogens. Indeed, towards the end of the review, the authors comment on the repeated observation that “the long hours of hard training that elite athletes undertake appear to make them more susceptible to upper respiratory tract infections”. In addition, the anti-inflammatory cytokine IL10, produced copiously during extensive exercise, limits the effectiveness of pathogen-specific innate and adaptive immune responses.
Therefore, at the conclusion of the article, I was left unsure as to the benefits of exercise as propounded by the authors, especially from an anti-inflammatory mechanistic viewpoint. However, it must be said that much of the above-mentioned evidence of the anti-inflammatory (and thereby, beneficial) effect of exercise is circumstantial, judging by the indirect nature of many of the effects, as well as the dependence of the said effects on intensity and duration of the exercise. Neither the interplay between pro- and anti-inflammatory cytokines, nor their relative dynamics, appear to be well-understood in the context of exercise.
For example, in this review, the authors have not touched upon the conflicting evidence that during exercise, contracting muscles give rise to localized inflammatory responses through synthesis of pro-inflammatory cytokines IL1β, TNF and IL6, whose levels are not transitory but remain high for days. There is also evidence that the pro-inflammatory cytokines may mediate muscle growth, as well as muscle repair following injury; in fact, IL6 has been identified as an essential regulator of hypertropic muscle growth2 via satellite cells (muscle stem cells) which are also involved in skeletal and cardiac muscle repair.3 Therefore, suppression of IL6 in the long term (as hypothesized in the anti-inflammatory model) cannot be beneficial to the host as a whole. The hypothesis of omental and muscle fat leading to a beneficial reduction of Adiponectin1 is also suspect, since the absence of Adiponectin expression causes contractile dysfunction and phenotypical changes in skeletal muscle.4 There also appears to be a strong relationship between exhaustive exercise, such as marathon running, and chronic low-grade inflammation induced by the massive systemic release of several pro-inflammatory cytokines and chemokines, such as IL6, IL8, G-CSF, M-CSF and MCP1 (which mediate recruitment and activation of inflammatory effector cells, neutrophils and monocytes), although host tissue damage may be restricted by compensatory mechanisms.5
In conclusion, benefits of regular exercise and physical activity are well observed. But perhaps it is best not to draw, yet, all-encompassing mechanistic conclusions involving inflammatory processes, because inflammation is a highly complex process fine-regulated by many factors; it may indeed not be possible to consider all those factors properly in context. Different types and intensities of physical exercise may well stimulate or suppress certain inflammatory processes, but their exact nature and consequences seem far from understood.
1. Gleeson, M., Bishop, N., Stensel, D., Lindley, M., Mastana, S., & Nimmo, M. (2011). The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease Nature Reviews Immunology, 11 (9), 607-615 DOI: 10.1038/nri3041
2. Serrano AL, Baeza-Raja B, Perdiguero E, Jardí M, & Muñoz-Cánoves P (2008). Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell metabolism, 7 (1), 33-44 PMID: 18177723
3. Grounds MD, White JD, Rosenthal N, & Bogoyevitch MA (2002). The role of stem cells in skeletal and cardiac muscle repair. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society, 50 (5), 589-610 PMID: 11967271
4. Krause MP, Liu Y, Vu V, Chan L, Xu A, Riddell MC, Sweeney G, & Hawke TJ (2008). Adiponectin is expressed by skeletal muscle fibers and influences muscle phenotype and function. American journal of physiology. Cell physiology, 295 (1) PMID: 18463233
5. Suzuki K, Nakaji S, Yamada M, Liu Q, Kurakake S, Okamura N, Kumae T, Umeda T, & Sugawara K (2003). Impact of a competitive marathon race on systemic cytokine and neutrophil responses. Medicine and science in sports and exercise, 35 (2), 348-55 PMID: 12569227