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Fats and Exercise Immunology

By Tammy Thomas, RD, M.Sc., CSCS
First published at www.johnberardi.com, Oct 25 2002.

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The contemporary Western diet consists of greater total fat and a 50-fold excess amount of the required omega-6 (n-6) polyunsaturated fatty acids. Although the consequences of overconsuming excess saturated fat in the diet are widely known, many may not realize that the overconsumption of n-6 fatty acids, and a lack of omega-3 (n-3) fatty acids, results in an undesirable n-6/ n-3 ratio of 25:1 compared to the 2:1 pre-industrial ratios. This unbalanced ratio may present insidious health issues much like those caused by excess saturated fat in the diet.

The major source of n-6 fatty acids is Linoleic acid (LA), and the major source of n-3 fatty acids is alpha- Linolenic acid (ALA). These two fatty acids are essential and are integral components of most human cell membranes (Cleland & James, 1997). n-6 derived LA will go on to form Gamma Linolenic acid (GLA) and Arachidonic acid (AA), with the latter of the two having great biological potency. Likewise, n-3 derived ALA forms eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both of which have markedly different activities than AA. EPA and DHA compete with AA for positions in the phospholipid membrane (Cleleand & James, 1997); however, if n-6 (LA)-derived Arachidonic acid were consumed in excess in the diet, the AA would most likely acquire the competitive binding sites. To prevent this, dietary EPA and DHA amounts should be increased so that these fatty acids would have a more equal opportunity at obtaining the positions in the cell membrane.

Once incorporated into the phospholipid bilayer, these fatty acids reside there until they are stimulated to be released from the membrane to undergo enzymatic degradation to the eicosanoids. Eicosanoids possess behaviors that are similar to hormones in that they can regulate hormone actions and their release. Among these eicosanoids are the prostaglandins (PGs), leukotrienes (LTs), and thromboxanes (TXs). Eicosanoids of the 2- and 4-series (e.g. PGE2, TXA2, and LTB4) are derived from AA and evoke a large immunological response, whereas eicosanoids of the 3- and 5-series (e.g. PGE3, TXA3, and LTB5) are derived from EPA and DHA and have low biological potency, and are said to be "inactive." In fact, the n-3 derived eicosanoids have 10-100 fold less capacity for evoking cellular responses than those derived from AA (Alexander, 1998). The eicosanoids can be strong modulators of smooth muscle contraction, renal and reproduction function, calcium ion mobilization, as well as inflammatory, traumatic, vascular, gut, and airway responses (Greenspan & Gardner p6).

The enhanced immunological response elicited by the AA-derived eicosanoids leads to the production of pro-inflammatory cytokines, whereas the production of these cytokines is reduced by EPA (Grimble, 1998). Cytokines are soluble proteins that are liberated from immune cells (mainly monocytes and macrophages) in response to infection, injury, or foreign substances. They are also involved in signalling between the cells of the immune system and play a role in modifying metabolism. The main pro-inflammatory cytokines are interleukin-1 (IL-1b), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-a) (Grimble, 1998). Interestingly, although cortisol can suppress the pro-inflammatory cytokines through negative feedback mechanisms, the pro-inflammatory cytokines increase the production of glucocorticoids (cortisol) and catecholamines (epi and norepi) by stimulating the sympathetic nervous system and corticotropin releasing factor (CRF). The combination of the catecholamines, cortisol, and cytokines enhance the metabolic adaptations that include gluconeogenesis and glycogenolysis, and consequent muscle catabolism (Grimble, 1998). However, this cytokine-induced cachexia is mostly observed in muscle-wasting diseases.

What is so interesting is that an increased production of these cytokines are correlated with a high dietary LA: ALA ratio, and there is evidence that increased dietary n-3 fatty acid consumption suppresses cytokine production and lymphocyte proliferation. Furthermore, the type of dietary fat influences cytokine production and activity (Alexander, 1998). For example, diets high in n-6 fatty acids enhance the production of IL-1 and TNF; however, diets high in the healthy n-3 and n-9 (oleic monounsaturated fat) fatty acids can decrease the inflammatory cytokines (Table 1).

Table 1. The effects of fatty acids on cytokine production. Missing arrows indicate no response or unknown response. Two-way arrows indicate equivocal findings. n-3 = ALA, n-6 = LA, n-9 = oleic acid, the monounsaturated fatty acids found predominantly in olive oil and canola oil.

A thorough review by Alexander (1998) revealed that studies using n-3 fatty acids interventions showed reductions in symptoms and significant improvements in myocardial infarction, coronary artery disease, hypertension, renal transplant, lupus and rheumatoid arthritis, inflammatory bowel disease, cancer and cachexia, burn patients, and post surgery and trauma (Alexander, 1998).

So what are good sources of n-3 fatty acids? The researchers purport that both flaxseed oil and fish oil provide immunological benefits. The ALA in flaxseed, flaxseed oil, and marine-derived n-3 polyunsaturated fatty acids (fresh or pill supplement form) displaces AA from the cell membrane and consequently reduces the production of the pro-inflammatory cytokines that are promoted through the oxidation of AA, injury, sepsis, and infection. Convincing evidence of these benefits have been observed in the Greenland Eskimo populations which consume large amounts of dietary fat, most of which is marine-derived. Interestingly, these people have a lower incidence of atherosclerosis, inflammatory, and autoimmune disease (Meydani, 1996).

Although human studies have shown that n-3 polyunsaturated rich oils reduce the production of the pro-inflammatory cytokines, IL-1, IL-6, TNF-a and IL-2, the studies with supplementation and exercise are inconclusive. One study (Toft et al. 2000) showed that n-3 supplementation had no effect on the cytokine levels after endurance exercise, despite the evidence of the incorporation of these fatty acids into the cell membrane. Yet, another group of researchers (Venkatraman et al. 2000), insist that the typical diets of athletes (15% fat, 65%CHO, 20% pro) are too negligible in fat, which results in antioxidant depression, decreases in anti-inflammatory immune factors, and negatively affected blood lipoprotein ratios. Therefore, dietary fat in adequate amounts is needed to ensure the intake of the essential fatty acids, n-6 and n-3, with n-3 lipids being responsible for decreasing the pro-inflammatory prostaglandins and cytokines (Venkatraman et al. 2000).

Moldoveanu and fellow researchers (2001) have compiled a comprehensive review of studies that look at the cytokine response to exercise. They have found that the various modes of exercise induce differing immune responses. Some types of exercise evoke IL-1 cytokine responses, but not TNF-a. While most types of exercise elicit an IL-6 response, IL-1 and TNF-a are not always induced. Furthermore, these cytokines seem to be summoned during intense exercise, such as cycling, sprinting, marathon running, and eccentric strength training. However, the role of n-3 fatty acid supplementation on cytokine suppression was not examined in this study (Moldoveanu et al. 2001).

Furthermore, the various types of exercises may confer differing immune responses. Marathon races (i.e., prolonged endurance exercise) instigate a substantial immune response, but the reasoning behind the immune response elicited by prolonged endurance exercise is unclear. Some believe that circulating immune cells may not necessarily indicate an increase in production and proliferation during exercise, but that exercise may be merely flushing the immune cells from their marginal pools. Or, another proposed mechanism behind the endurance exercise-induced cytokine response is that during long-duration exercise (over 2hours), heat-stroke ischemia of the gastrointestinal tract increases permeability to the gut to allow penetration of bacterial toxins. The release of these toxins, thus, trigger the inflammatory and immune response, that resembles the response of sepsis and infection.

In contrast with endurance exercise, strength training may evoke entirely different mechanisms of the immune response. Unlike endurance exercise, researchers draw a line of distinction with eccentric exercise in that it induces cytokine release that mediates muscle building and hypertrophy, and that "their presence seems a requirement for regeneration of skeletal muscle tissue (Moldoveanu, 2001). In strength training, the paradoxical relationship of immune cells participating in tissue and debris clearance and subsequent tissue repair is well known. Although, throughout the literature there is mention of immune cell disruption and redistribution from marginal pools caused from the shear force involved in intense muscle exercise, there is nothing about endotoxin-mediated immune responses involved in strength training.

The idea that the various modes of exercise that mediate the same immune responses can result in conflicting responses is intriguing, and may leave us wondering, are the immune responses triggered by the various types of exercise treated unequally? Is this a case of host defense versus repair process and subsequent hypertrophy? This fascinating dichotomy suggested by the researchers requires more exploration to tease out the alternative immune mechanisms and kinetics that differ that occur during the various modes of exercise (Moldoveanu). Currently, the field of exercise immunology is fairly young, and all the physiology mechanisms and dietary impacts are not yet well understood.

About the Author

Tammy Thomas is a registered dietitian, a certified strength and conditioning specialist (CSCS), and has earned a Master's degree in Exercise Science focusing on Nutritional and Exercise Biochemistry. Currently she does training and nutrition writing and consulting for individuals with rheumatoid arthritis and other autoimmune diseases. She can be reached at tammy@proactivitysupport.com.

References

Alexander, J. W. (1998). Immunonutrition: The role of w-3 fatty acids. Nutrition,14: 627-633.

Cleland, L.G., James, M.J. (1997). Diet and Arthritis: Rheumatoid arthritis and the balance of dietary n-6 and n-3 essential fatty acids. British Journal of Rheumatology, 35: 513-514.

Erikson, K.L., Hubbard, N.E. (1996). Dietary fish oil modualtion of macrophage tumoricidal activity. Nutrition, 12 (1)Suppl: S34-S38.

Greenspan, F.S., Gardner, D.G. Basic & Clinical Endocrinology:6th Edition. Lange Medical Books/McGraw Hill; San Francisco, Ca: 2001.

Grimble, R.F. (1998). Nutritional modulation of cytokine biology. Nutrition,14: 634-640.

Meydani, S.N. (1996). Effect of (n-3) polyunsaturated fatty acids on cytokine production and their biologic function. Nutrition, 12, (Suppl 1): S-8S14.

Moldoveanu, A.I., Shephard, R.J., Shek, P.N. (2001). The cytokine response to physical activity and training. Sports Medicine, 31 (2): 115-144.

Rowbottom, D.G., Green, K.J. (2000). Acute exercise effects on the immune system. Medicine & Science in sports & Exercise, 32 (7) Suppl:S396-S405.

Toft, A.D., Thorn, M., Ostrowski, K., Asp, S., Moller, K., Iversen, S., Hermann, C., Sondergaard, S.R., Klarlund Pedersen, B. (2000). N-3 polyunsaturated fatty acids do not affect cytokine response to strenuous exercise. Journal of Applied Physiology, 89:2401-2406.

Venkatraman, J.T., Leddy, J., Pendergast, D. (2000). Dietary fats and immune status in athletes: clinical implications. Medicine & Science in Sports & Exercise, 32 (7) Suppl: S389-S395.