The Il6 Response To Exercise

Interleukin-6 is produced in larger amounts than any other cytokine in relation to exercise. IL-6 is produced by many different cells, but the main sources in vivo are stimulated monocytes/macrophages, fibroblasts and vascular endothelial cells [28], indicative of its role in modulation of the immune system. Other cells known to express IL-6 include keratinocytes, osteoblasts, T cells, B cells, neutrophils, eosinophils, mast cells, smooth muscle cells [28] and skeletal muscle cells [29]. Until now, IL-6 has been considered a cytokine with immunomodulatory effects and immune cells have been regarded as the main cell source of production. However, during the past few years it has also been demonstrated that the level of circulating IL-6 increases dramatically (up to 100 fold) in response to exercise [2,30,31]. Northoff and Berg [32] were the first to suggest that IL-6 might be involved in the generation of the acute phase response post-exercise. They found an increase in IL-6 levels immediately after a marathon run. The finding of increased levels of IL-6 after exercise is a remarkably consistent finding [4-6,8-11,14,33-46]. The finding of markedly increased levels of IL-6 after strenuous exercise has consistently been found in many studies [4-6,9,14,32,34,35-37,47-48]. A two-fold increase in plasma-IL-6 was demonstrated after six minutes intense exercise [43]. In treadmill running, the IL-6 level in blood was significantly enhanced 30 min after the start of running with the IL-6 peaking at the end of 2.5 hours of running [5]. In other studies where IL-6 was not measured during the running but at several time points after, maximal IL-6 levels were found immediately after the exercise followed by a rapid decline. Thus, following a marathon run maximal IL-6 levels (100 fold increase) were measured immediately after the 3-3.5 hour race [4,6]. Data from the Copenhagen Marathon (1996, 1997 and 1998, n=56) suggest that there is a correlation between the intensity of exercise and the increase in plasma IL-6 LI 1J. A previous study suggested that the appearance of IL-6 in the circulation was related to muscle damage [49], however, more recent studies clearly demonstrate that muscle contractions without any muscle damage induce marked elevation of plasma IL-6 [5,6,50,51 ]. In a recent study, we demonstrated that despite marked increases in both creatine kinase and myoglobin five days after eccentric exercise, the plasma IL-6 peaked into recovery only a few folds in both groups [51]. Apart from exercise intensity, duration and mode, it has also been suggested that the cxcrcise-induced increase in plasma IL-6 is related to the sympatho-adrenal response [34,45,52]. A study performed in animals suggested that the increase in epinephrine during stress was responsible for the increase in IL-6 [53]. However, recent data from our group showed that when adrenaline was infused into volunteers to closely mimic the increase in plasma-adrenaline during 2.5 h of running exercise, plasma IL-6 increased only 4-fold during the infusion, but 30-fold during the exercise [42], Thus, it seems that epinephrine only plays a minor role in the exercise-induced increase in plasma IL-6. It was previously demonstrated that peak plasma IL-6 during exercise correlated with plasma lactate [5].

2.1. Exercise-induced IL-6 - where is it produced?

A number of studies [48,54] have demonstrated that IL-6 mRNA in monocytes, the blood mononuclear cells responsible for the increase in plasma IL-6 during sepsis [2], did not increase as a result of exercise. While determining intracellular cytokine production, it was demonstrated that the number, percentage and mean fluorescence intensity of monocytes staining positive for IL-6 either does not change during cycling exercise [55], or in fact, decreases during prolonged running [8], To test the possibility that working muscle produces IL-6, muscle biopsies were collected before and after exercise [4], Before exercise, IL-6 mRNA could not be detected in muscle but we did detect IL-6 in the post-exercise samples. The observation that intramuscular IL-6 gene expression increases in skeletal muscle in response to exercise, was confirmed in a rat exercise model using the quantitative competitive RT-PCR method [56]. In this model, rats were subjected to electrically-stimulated eccentric or concentric contractions of one hind leg, while the other leg remained at rest. Both the eccentric and concentric contractions resulted in elevated levels of IL-6 mRNA in the exercised muscle, whereas the level in the resting leg was not elevated. It appears, therefore, that the local IL-6 production is connected with contracting muscle, and is not due to a systemic effect, because IL-6 mRNA was elevated only in the muscle from the exercising leg and not in the resting leg. As discussed, in these previous studies, we were unable to detect IL-6 mRNA in resting skeletal muscle. Of note, the finding of similar levels of IL-6 mRNA in both concentric and eccentric exercised muscle [39,56] supports the idea that the cytokine production cannot be as closely related to muscle damage as first thought. More recent studies [39,41] utilising the real time RT-PCR technique have shown that IL-6 mRNA is present in resting skeletal muscle and is enhanced up to 30-fold in contracting muscle, thus indicating that exercise is responsible for the IL-6 gene-induction. Recently, it was shown that the IL-6 gene is not only activated in working muscle, but that the IL-6 protein is released in large amounts from a contracting limb and markedly contributed to the exercise-induced increase in arterial plasma concentrations [40]. By obtaining arterial-femoral venous differences over an exercising leg we found that exercising limbs released IL-6. In addition, during the last two hours of exercise the release per unit time was approximately 17-fold higher than the amount accumulating in the plasma. We have recently confirmed that IL-6 is released from a contracting limb during both knee extensor [41] and bicycle [57] exercise. Although IL-6 appears to be produced in the contracting skeletal muscle, it is still not fully clear which cell type within the muscle is responsible for the production. While myoblasts have been shown to be capable of producing IL-6 [58,59], endothelial cells [60], fibroblasts [59] and smooth muscle cells [61] have also been shown to produce IL-6 under certain circumstances. In order to determine which cells produce the IL-6, Keller and colleagues isolated nuclei from muscle biopsies obtained before, during and after exercise. Using RT-PCR it was demonstrated that the transcription rate for IL-6 increased rapidly and markedly after the onset of exercise [62], This suggested that a factor associated with muscle contraction increases the IL-6 transcriptional rate. The finding that human muscle cell lines can be stimulated to produce IL-6 further supports the hypothesis that myocytes are the origin of IL-6. Other sources of IL-6 include the human brain, which releases a small amount of IL-6 during exercise [65], tendons [66], and adipose tissue [67], However, it appears that most of the IL-6 produced during exercise originates from the contracting limbs. The recent finding that muscle fibres express high amounts of IL-6 protein after exercise, but not at rest, strongly suggests that muscle fibres per se are the source of origin [68].

2.2. Carbohydrate loading, muscle glycogen content and IL-6 production.

Several studies have reported that carbohydrate ingestion attenuates elevations in plasma IL-6 during both running and cycling [34,45]. Recently, it was reported that carbohydrate ingestion did attenuate the increase in plasma IL-6 in response to both cycling and running [39]. However, the IL-6 gene expression in the contracting muscles was not affected by carbohydrate ingestion. Thus, during exercise carbohydrate ingestion exerts its effect at the post-transcriptional level of IL-6, although it is not known yet whether this effect occurs through translation and/or the release of IL-6.

In a recent study, an elevated plasma IL-6 response was observed when subjects exercised in a glycogen-depleted state [65]. Subjects completed 1 h of single-legged bicycle exercise followed by 1 h of double-arm cranking 16 h prior to performing 4-5 h of exhaustive two-legged knee extensor exercise. In the intervening 16 h, subjects consumed a low carbohydrate diet. This protocol was designed to deplete glycogen content in one leg and it allowed us to test the hypothesis that pre-exercise glycogen availability affected IL-6 production. The model was advantageous because delivery of substrates and hormones to each limb was the same. Subjects commenced exercise with a 40% lower glycogen content in the low-glycogen compared with the high-gly-cogen leg [41]. It was found that in the post-exercise samples, those with the lowest glycogen content expressed the highest levels of IL-6 mRNA. In addition, the release of IL-6 from the low-glycogen exercising leg occurred after only 60 min of exercise whereas it occurred after 120 min in the other limb [41]. Thus, muscle glycogen content was a determining factor for the production of IL-6 across contracting limbs. However, one potential concern from this previous study was that the exercise performed the day before would influence the results the day after. To rule out this possibility, subjects performed exercise on two different occasions, once with a normal and once with a low pre-exercise muscle glycogen content [62]. The study demonstrated that prolonged exercise activates transcription of the IL-6 gene in skeletal muscle of humans, a response that was dramatically enhanced under conditions in which muscle glycogen concentrations were low. Therefore, pre-exercise intramuscular glycogen content appears to be an important stimulus for the IL-6 gene transcription.

2.3. Biological roles of muscle-derived IL-6

As discussed, the increase in the IL-6 mRNA [41,62], its nuclear transcriptional activity [62] and protein release from skeletal muscle [41] is augmented when muscle glycogen availability is reduced. Furthermore, the increased expression of IL-6 was associated with increased glucose uptake during exercise [41], This suggests that IL-6 may be involved, at least in part, in mediating glucose uptake during exercise. Of note, work from Stouthard and co-workers have shown a more direct relationship between IL-6 and glucose transport. In the first of these studies Stouthard et al. [66] demonstrated that infusion of recombinant human IL-6 (rhIL-6) into human subject, increased whole body glucose disposal and subsequent oxidation compared with a control trial. Even though endogenous glucose production was increased with rhIL-6 infusion, the metabolic clearance rate of glucose was higher in this trial suggesting that relative hypergly-caemia was not responsible for the augmented glucose disposal. Moreover, in a follow up study, Stouthard et al. [67] demonstrated that IL-6 increased both basal and insulin stimulated glucose uptake in cultured 3T3-L1 adipocytes. These authors concluded that IL-6 acted by increasing glucose transporter intrinsic activity. Recent evidence from others also provides a mechanism as to how IL-6 may act to increase glucose uptake. Increased glucose transport was found in jejunal tissue incubated with IL-6 compared with controls [68], Moreover, IL-6 also seems to be able to increase the absorption of glucose in the gut, thereby increasing the plasma glucose levels [68]. Although speculative, these studies suggest the possibility that muscle-derived IL-6 may act, at least in part, to contribute to contraction-mediated glucose uptake.

Beside the possible glucoregulatory effect of IL-6, emerging evidence suggests that this cytokine may also be involved in other metabolic pathways. Concomitantly with the increase in liver glucose output during IL-6 infusion, Stouthard et al. [67] found an increase in circulating free fatty acids (FFA) with rhIL-6 infusion. It must be noted, however, that in this previous study, epinephrine was elevated and, therefore, the authors could not determine whether IL-6 acted directly on adipocytes, since epinephrine is a powerful lipolytic hormone. Infusion of IL-6 into rats increased serum triglyceride and FFA levels in a dose-dependent manner [69]. The hyper-triglyceridaema was due to increased secretion by the liver and not decreased clearance. In a recent study from our group (unpublished data), IL-6 was infused into normal healthy volunteers at a dose that did not influence catecholamine and glucagon levels. Physiological concentrations of rhIL-6 induced a pronounced lipolysis indicating that IL-6 should be classified as a novel lipolytic hormone. The suggestion that IL-6 is strongly involved in fat metabolism is supported by a very important study be Wallenius et al. [70], who recently demonstrated that IL-6-deficient mice developed mature-onset obesity compared with wild type control mice. In addition, when the mice were treated with IL-6 for 18 days, there was a significant decrease in body weight in the transgenic, but not wild-type mice. Thus it is evident that IL-6 is a powerful lipolytic fac_tor and suggests that during exercise, the increase in arterial FFA concentration is mediated at least in part by IL-6 released from the muscle. Hence, it is likely that muscle-derived IL-6 acts in a neuro-endocrine hormone-like manner.

Today, interleukin IL-6 is thought by many authors to be the link between inflammation, obesity, stress and coronary heart disease [71]. However, given the finding that working muscles produce and release IL-6 in large amounts and the many beneficial effects of physical exercise on health [30], it is hard to believe that muscle-derived IL-6 is detrimental to health. An alternative explanation is that TNF-a, rather than IL-6, is the actual driver behind the metabolic syndrome. Thus, since TNF induces the production of IL-6, a high concentration of TNF will induce a high production of IL-6. Increased levels of both TNF-a and IL-6 have been observed in ageing [72], in obese individuals [73] and in non-insulin-dependent diabetes mellitus [74-77]. Furthermore, in several population-based studies, plasma concentrations of IL-6 have been shown to predict total and cardiovascular mortality [78], Nevertheless, although adipose tissue produces and releases both TNF-a and IL-6 [79,80], there is experimental evidence that adipose TNF-a-expression, but not expression of IL-6, plays a mechanistic role in insulin resistance [81], Hotamisligil [80] was the first to report a close relationship between increased adipose tissue TNF-a-expression and features of insulin resistance in rodent models of obesity and type 2 diabetes mellitus. The mechanisms by which TNF-a induces insulin resistance may be several. Long-term exposure of differentiated human adipocytes to TNF-a in vitro resulted in marked reduction of GLUT-4 [82] although later studies suggested that TNF-a-mediation of GLUT-4mRNA expression may not be responsible for insulin resistance [83], TNF-a impairs insulin receptor signalling [84], TNF-a also inhibits lipoprotein lipase (LPL) and stimulates lipolysis in adipocytes [85]. The resulting increase in circulating nonesterified fatty acids would be expected to contribute to insulin resistance [86], TNF-a was elevated in elderly patients with atherosclerosis compared with age-matched subjects without this diagnosis [72]. However, although TNF-a correlated with IL-6 [72], the latter cytokine was not associated with atherosclerosis. TNF-a and IL-6 are tightly linked, with TNF-a stimulating IL-6 production. On the other hand, in vitro studies [87] as well as animal studies [88,89] suggest that IL-6 may inhibit TNF-a production. Therefore, exercise-induced IL-6 production may inhibit TNF-a-induced insulin resistance.

Finally, exercise-induced IL-6 production may also have an indirect role in mediating leukocyte trafficking of natural killer (NK) cells and neutrophils [90]. As described below, it appears that the acute exercise effect on NK cells is mediated by catecholamines, in particular epinephrine [42]. However, the post-exercise decline of NK cell activity and post-exercise neutrophi-lis is mediated by Cortisol. The latter hormone is of particular interest, if the exercise is of long duration. The increase in Cortisol is mediated by IL-6 [91]. Linking exercise-induced changes in NK cells and neutrophils to an effect of IL-6 on Cortisol production, is further supported by several studies demonstrating that carbohydrate loading during exercise attenuates the exercise effect on function [34,92,93],

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