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Exercise and IL-6 ani-inflammatory effect

What you need to know about exercise and inflammation

Saul Yudelowitz BSc (Hons)

Inflammation and especially chronic low grade inflammation has been proposed as a key factor to insulin resistance, which often leads to cardiovascular disease and obesity as well as neurodegenerative disease (Dandona et al 2004). Low grade chronic inflammation (LGCI) is reflected by an increase in systemic levels of

C-reactive protein (CRP), (Ross 1999). A Finnish study by (Tuomilehto et al 2001) found that modifying lifestyle, reduced the risk of type 2 diabetes by 58% in comparison with no life style modifications and just the use of Metformin, which reduced the risk by 31%. In this research paper lifestyle changes included regular exercise and nutritional choices. The results strongly associate the protective effects of exercise against type 2 diabetes. There is also a great deal of evidence of the physiological effects of exercise on coronary heart disease (CHD), (Taylor et al 2004). Local inflammation is accompanied by a systemic response known as the acute phase response (Petersen & Pedersen 2005). This includes CRP and can be mimicked by the injection of cytokines tumor necrosis factor-alpha (TNC-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6). In response to acute infection/trauma, cytokine and cytokine inhibitor levels increase 3-4 fold and then decrease after recovery. LGCI is defined as a 2-3 fold increase in systemic concentrations of TNC-alpha, IL-1, IL-6, IL-1ra, sTNF-R and CRP (Maughan et al 2009).

The likely stimulus of TNF secretions in LGCI is adipose tissue. Cytokine response to exercise is different to that elicited by infection. IL-6 is the first cytokine released in an exponential manner, increasing up to 100 fold in response to exercise (Pedersen & Hoffman-Gotez 2000; Pedersen et al 2001; Febbraio & Pedersen 2002;

Suzuki et al 2002). The classic pro-inflammatory cytokines, TNF-alpha and IL-1beta do not increase with exercise. This provides evidence that exercise induced and infection induced cytokines differ from each other. The post exercise induced cytokines have anti inflammatory effects (Pedersen & Febbraio 2008). The term ‘exercise factor’ has been associated with this effect. The main proposed candidate for the exercise factor is muscle derived IL-6, which is a link between skeletal muscles and peripheral organs as adipose tissue and IL-8, which is released from skeletal muscles to effect the muscle locally. Muscle derived IL-8 is proposed to be involved in exercise induced angiogenesis. Muscle derived cytokines that fulfill the exercise factor are termed ‘myokines’

(Akerstrom et al 2005). IL-6 plasma levels increase in an exponential manner with exercise and is related to exercise intensity, duration, muscle mass recruited and endurance. A two fold increase in plasma IL-6 levels is seen after 6 minutes of maximal rowing. During prolonged endurance exercises IL-6 does not increase until later during the exercise (Pedersen & Fischer 2007). This suggests a correlation between intensity of the exercise and the increase in plasma IL-6 levels (Pedersen & Fischer 2007).

The amount of muscle mass recruited also plays a vital role; it has been observed that there are higher levels of IL-6 from running than cycling. The type of muscle contraction also has an effect on IL-6 levels. During prolonged eccentric contraction IL-6 levels only peaked long after the exercise session while concentric muscle contractions resulted in IL-6 levels peaking at the end of the exercise session (Pedersen & Fischer 2008).

Ingestion of carbohydrates reduces the plasma levels of IL-6 without decreasing intramuscular expression of IL-6 mRNA. IL-6 release is regulated by substrate availability (Febbraio et al 2003). Low muscle glycogen concentrations enhance IL-6 mRNA and transcription rates. Therefore it can be concluded that glycogen content is a determining factor for the production of IL-6 in contracting muscles. Skeletal muscle is the main source of IL-6 during exercise, while monocytes are not the major contributors to the IL-6 response during exercise. Small amounts of IL-6 are released from adipose tissue, the brain and peri-tendon tissue may also release IL-6 in response to exercise. IL-6 released from contracting muscles act like a hormone to mobilize extracellular substrates and/or argument substrate delivery during the exercise. IL-6 is regulated in an autocrine manner (Keller et al 2003). Acute exercise induces IL-6 receptor expression after exercise, after a 10 week exercise period the IL-6 receptor mRNA production was increased in skeletal muscle which results in a sensitization of skeletal muscle to IL-6 at rest. There is a large amount of evidence to suggest that TNF-alpha has a significant role in the metabolic syndrome (Plomgaard et al 2005). Patients with diabetes have high TNF levels in plasma. Adipose tissue produces TNF-alpha which is the main source of the cytokine in diabetic patients. TNF-alpha impairs the insulin stimulated glucose storage in muscle (Halse et al 2001). Obese mice with the knock out of TNF-alpha gene are protected from insulin resistance (Uysal et al 1997). TNK-alpha has an inhibitory effect on insulin signaling and impairs glucose uptake and metabolisim. There is also a strong link between insulin resistance and low grade systemic inflammation

(Plomgaard et al 2005). TNF-alpha plays a key role in linking insulin resistance to vascular disease. During the resting state IL-6 administration does not impair whole body glucose disposal, net glucose uptake or increased endogenous glucose production in healthy young humans (Lyngso et al 2002; Steensberg et al 2003; Petersen et al 2004). In patients with type 2 diabetes plasma insulin levels decreased with IL-6 infusion suggesting a sensitizing effect of IL-6 (Petersen et al 2004). IL-6 increased glucose infusion rates (Carey et al 2006) and glucose oxidation without affecting the suppression of endogenous glucose production during hyperinsulinemic euglycemic clamp in healthy humans (Kim et al 2004). IL-6 may exert inhibitory effects on TNF-alpha (Peterson & Pedersen 2005). The anti-inflammatory effects of IL-6 are also seen by IL-6 stimulation of IL-1ra and IL-10 production; these cytokines in circulation after exercise contribute to the anti-inflammatory effect. Infusion of rhIL-6 into humans increases cortisol plasma levels which also ultimately has an anti-inflammatory effect. Muscle derived IL-6 mediates this effect. Given the biological differences of TNF-alpha and IL-6 and that TNF-alpha can trigger IL-6 release, one theory that holds is that adipose tissue derived TNF-alpha is the driver behind the metabolic syndrome and increased levels of systemic IL-6 reflects locally produced TNF-alpha (Petersen & Pedersen 2005). There is evidence that IL-6 suppresses TNF-alpha production in humans (Starkie et al 2003) and it is likely that the anti-inflammatory effects of exercise, which is mediated from muscle derived IL-6 offer protection against TNF induced insulin resistance.


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