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Nov 14, 2014 - and Akhlaq A. Farooqui. © 2015 John Wiley & Sons, Inc. Published 2015 by John Wiley & Sons, Inc. 183 ...... Amthor H, Nicholas G, McKinnell I, Kemp CF,. Sharma M, Kambadur R, .... 36: 574–576. 134. Smith AG, Muscat GE.
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Please note that the references [73, 74, 121, 166, 161, 109, 49, 111, 112] are repetition of references [8, 9, 92, 157, 154, 84, 32, 106, 96], respectively. It will be renumbered after providing the missing citation of the reference 149. Please provide the citation for reference 149 in the text.

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17 UND Life Sciences, Federal Way, WA, USA

17.1  Introduction

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Physically active people have a life span that is 5 years longer than that of physically inactive people. The expected lifetime without long‐standing illness is increased by approximately 8 years in physically active people [1]. Physical activity decreases the risk of obesity, type 2 diabetes, cardiovascular disease, colon cancer, postmenopausal breast cancer, dementia, and depression [2–7] (see Fig. 17.1). Exercise is anti‐inflammatory in nature [8–11]. In other words, physical activity leads to reduction in the accumulation of visceral fat and depresses inflammatory pathways that promote development of insulin resistance, atherosclerosis, neurodegeneration, and tumor growth, diseases that are due to physical inactivity. This beneficial action of exercise implies that, possibly, muscle produces bioactive molecules that could exert autocrine, paracrine, or endocrine effects and allows muscle to communicate to other organs [12] (see Fig. 17.2). Contracting human skeletal muscle releases significant amounts of interleukin (IL)‐6, IL‐1 receptor antagonist (IL‐1ra), the anti‐inflammatory cytokine IL‐10, chemokines, IL‐8, macrophage inflammatory protein 1a (MIP‐1a), MIP‐1b, and tumor necrosis factor (TNF)‐α. Of all, secretion of IL‐6 into the circulation

is by far the most marked and precedes that of the other cytokines [9]. In addition to skeletal muscle several other tissues also produce IL‐6. It appears that there are distinct differences in the actions exerted by IL‐6 depending on its source and the amount produced. IL‐6 signaling in macrophages is dependent upon the NF‐κB signaling pathway, whereas intramuscular IL‐6 expression is regulated by Ca2+/nuclear factor of activated T cells (NFAT) and glycogen/p38 mitogen‐activated protein kinase (MAPK) pathways. Thus, IL‐6 produced by macrophages induces an inflammatory response, whereas IL‐6 released by muscle cells does not activate the proinflammatory pathways, which may explain differences in the actions of IL‐6 released by the muscle and macrophages.

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Molecular, Biochemical, and Physiological Basis of Beneficial Actions of Exercise

17.2  IL‐6 has both Pro‐ and Anti‐ Inflammatory Actions In addition, exercise‐induced skeletal muscle release of IL‐6 is several 100‐fold higher compared what is released by macrophages (see Fig. 17.3). In resting healthy humans, plasma IL‐6 is about 1–2 pg/ml or less [11]. On the other hand, exercise induces an acute increase in IL‐6 production and

Diet and Exercise in Cognitive Function and Neurological Diseases, First Edition. Edited by Tahira Farooqui and Akhlaq A. Farooqui. © 2015 John Wiley & Sons, Inc. Published 2015 by John Wiley & Sons, Inc. 183

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Fig. 17.1  Physical activity decreases visceral fat; suppresses inflammatory pathways; restores immune dysfunction to normal by decreasing insulin and leptin resistance; prevents atherosclerosis and neurodegeneration; suppresses tumor growth by enhancing the formation/conversion of white adipose tissue to brown adipose tissue, PGC‐1α expression in muscle, and increasing the formation and release of irisin that increases energy expenditure; augments BCL2 expression; increases autophagy; increases BDNF levels; decreases the expression of myostatin; and upregulates the immune response, events that are eventually responsible for its beneficial actions. (Adopted from Das UN. Impact of exercise intervention on inflammation, immunity, and diseases. In: Exercise therapy in adult obesity, Hansen Dominique (ed.), Nova Science Publishers: New York, 2013.)

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release by the working muscle [12–16]. In contrast, exercise training (regular and moderate exercise) leads to reduced circulating IL‐6 levels and IL‐6 mRNA expression even in patients with cardiac disease [17–19]. In addition, changes in levels of IL‐6 receptor expression seen due to exercise training leads to an increase in IL‐6 sensitivity in skeletal muscle [20, 21]. In patients with type 2 diabetes and in elderly people, circulating levels of IL‐6 are about two to threefold higher than those measured in young and adult healthy individuals [22–25]. This 2–3‐fold increase in IL‐6 seen in type

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2 diabetes mellitus and elderly subjects is in contrast to the situation in exercise, where IL‐6 levels increase acutely up to 100‐fold [15, 16], concentrations that are equivalent to those seen in severe infections [26] (see Fig. 17.3; in normal subjects, the plasma levels of IL‐6 is ~1–2 pg/ml; in type 2 diabetics, it is ~3–6 pg/ml; in subjects with sepsis, it is ~200–300 pg/ml or even higher, while during exercise, the IL‐6 levels tend to be ~100–200 pg/ml [27, 28]). This may explain the paradoxical situation wherein IL‐6 acts as a proinflammatory molecule in some instances and at other times

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Fig. 17.2  Biological role of contraction‐induced secretion of IL‐6, IL‐15, TNF‐α, BDNF, myostatin protein, and irisin. Skeletal muscle IL‐6 into the circulation during exercise that, in turn, exerts its effects both locally within the muscle (e.g., through activation of AMP‐activated protein kinase, AMPK) and systemically when released into the circulation and acts on several organs in a hormonelike fashion. The brain, gastrointestinal tract, and adipose tissue also produce their own peptides/hormones/circulating factors during exercise that bring about the beneficial actions of exercise. It is predicted that there is a close interaction(s) among these tissues/organs/systems and their soluble factors that act on the whole body. Different tissues/organs produce different molecules sometimes overlapping substances. All these factors ultimately improve overall health. (Adopted and modified from Das UN. Impact of exercise intervention on inflammation, immunity and diseases. In: Exercise therapy in adult obesity, Hansen Dominique (ed.), Nova Science Publishers: New York, 2013.) (See insert for color representation of the figure.).

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shows anti‐inflammatory actions. This apparently paradoxical action of IL‐6 seems to be dependent on the source (muscle vs. immune cell), the degree of its elevated levels (chronic vs. acute rise), and the amount of IL‐6 secreted (low vs. high). Thus, IL‐6 may show both pro‐ and anti‐inflammatory actions depending on the source (muscle vs. macrophages), amount of secretion (low vs. high), and duration of secretion (acute vs. chronic). Athletes who performed an exhaustive exercise stress test for 68 minutes showed elevated levels of IL‐6 and soluble IL‐2 receptor (sIL‐2R) 1 hour after the run in both serum and urine samples, while TNF‐α in serum was increased, whereas IL‐2 in urine was decreased after the exercise. In cell culture studies

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using peripheral leukocytes obtained from these volunteers, LPS stimulation‐induced release of TNF‐α, IL‐1, and IL‐6 was suppressed 1 hour after exercise. Also, the Con‐A‐induced and LPS‐induced release of IFN‐γ and the PHA‐induced release of IL‐2 were suppressed 1 hour after exercise. In contrast, Con‐A‐ induced release of IL‐2 was mildly increased after the exercise. These results suggest that exercise activates the immune system that is immediately counterregulated [29]. Twenty hours after the exercise, most of the observed changes reverted to pre‐exercise levels. Thus, IL‐6 levels that increase acutely compared to other cytokines during exercise has a beneficial effect on muscle metabolism and mediates the anti‐inflammatory actions of exercise [30, 31].

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Fig. 17.3  Relationship between plasma IL‐6 levels and various disease states. In normal subjects, the plasma IL‐6 levels will not be more than 1–2 pg/ml. In infections and in sepsis, the plasma levels are high approximately 100–170 pg/ml, which will drop to normal following recovery from infection and sepsis. In type 2 diabetics, the plasma levels of IL‐6 is approximately 3–6 pg/ml. On the other hand, during exercise, the plasma IL‐6 levels tend to be approximately 200–300 pg/ml and will drop to normal within 24 hours after exercise (See insert for color representation of the figure.).

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Furthermore, overnutrition induced insulin and leptin resistance through IKKβ activation, and endoplasmic reticulum (ER) stress in the hypothalamus was found to be suppressed by physical exercise by a mechanism dependent upon IL‐6. This is supported by the observation that disruption of hypothalamic‐specific IL‐6 action blocked the beneficial effects of exercise on insulin and leptin resistance. This beneficial action of physical activity seems to involve the anti‐inflammatory protein IL‐10, which is an inhibitor of IKKβ/ NF‐κB signaling and ER stress. Both exercise and recombinant IL‐6 (rIL‐6) enhanced IL‐10 expression to suppress hyperphagia‐related obesity. Moreover, mice deficient in IL‐6 and IL‐10 failed to reverse IKKβ and ER stress [32]. These results suggest that IL‐6 and IL‐10 interact with each other to bring about the beneficial actions of enhancing insulin and leptin signaling both in the peripheral issues and hypothalamus. In addition, it was reported that corticosteroids may have little influence on the secretion and action of IL‐6 [33]. For instance, it was noted that administration of a pharmacological dose of hydrocortisone to healthy human volunteers suppressed

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the production of IL‐1β, TNF‐α, and IL‐6, whereas administration of a physiological dose of hydrocortisone suppressed only TNF‐α production. In this context, it is interesting to note that stress‐induced levels of glucocorticoids, achieved during exercise at 100% maximal oxygen utilization, suppressed IL‐1β and TNF‐α production, but were without effect on IL‐6 production. Circadian variations of cortisol were associated with decreased TNF‐α production but were without effect on IL‐1β or IL‐6 production. These studies indicated and challenged the concept that glucocorticoids consistently suppress proinflammatory cytokine production (and thus bring about their anti‐inflammatory action) and indicated a hierarchy of sensitivity, with TNF‐α having the greatest sensitivity, IL‐1β having intermediate sensitivity, and IL‐6 being resistant. The resistance of IL‐6 production to glucocorticoid suppression is compatible with the idea that this cytokine (IL‐6) has both proinflammatory and anti‐ inflammatory actions and supports the contention that exercise‐induced increase in IL‐6 may have anti‐inflammatory actions that could be responsible for the anti‐inflammatory potential of exercise. These results emphasize the fact that physiological

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17.3  Interaction(s) between Cortisol and Cytokines and Its Relevance to Sepsis

by  the initial hyperinflammatory response and subsequent immunosuppression whose duration is  variable in different subjects, suggesting that restoring the initial hyperinflammatory and subsequent immunosuppression to normal could be of significant benefit in sepsis. In other words, it implies that failure to suppress inappropriate initial hyperinflammatory response and prevent subsequent immunosuppression could lead to failure to recover from tissue injury and/or damage to various target organs that may render the patient to succumb to sepsis (see Fig. 17.4). In a study [38] aimed at investigating the endogenous adrenocortical response to sepsis, it was noted that in 37 patients with septic shock (53 ± 3 years of age), plasma cortisol concentrations were 50.7 μg/dl, range of 15.6–400, compared to normal values (10–20 μg/dl) after 11 ± 2 hours after shock commenced. Neither patients who reversed their shock nor those who survived to hospital discharge had significantly different plasma cortisol concentrations from those who did not. Patients with Gram‐positive infections had increased cortisol levels compared with those who had Gram‐negative infections (median 83 μg/dl, range 32–400, vs. median 44 μg/dl, range 16–81, respectively; p 34 pg/ml) in 69% of the patients with sepsis versus 33% of those without sepsis, in 71% of the patients who died versus only 31% of the survivors, and in only one healthy normal

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concentrations of hydrocortisone (which occur ­during exercise) suppresses TNF‐α production (and thus, the proinflammatory action of this cytokine is abrogated during exercise), whereas when pharmacological doses of hydrocortisone is used (as it happens during the management of inflammatory conditions such as lupus, rheumatoid arthritis, scleroderma, early sepsis, etc.), inadvertently, one is suppressing the production of IL‐6 that serves as a physiological anti‐inflammatory molecule (via enhancing IL‐10 and suppressing IKKβ/NF‐κB signaling and ER stress) and, thus, paving the way for the persistence and progression of inflammatory events. This implies that, in order to know the influence of hydrocortisone (and other steroids) administered on the inflammatory events, one could measure plasma levels of TNF‐α, IL‐1β, IL‐10, and IL‐6 to know the status of the inflammatory disease(s) [34]. This is especially applicable to the inflammatory and immunosuppressive events that occur in sepsis (see Fig. 17.5).

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Sepsis is a systemic inflammatory response syndrome that occurs during severe infection and kills more than 200,000 people in the United States annually. Mortality in sepsis is due to multiple organ dysfunctions (multiorgan dysfunction syndrome (MODS)) (reviewed in Ref. [35]). Sepsis can occur in two distinct clinical syndromes, acute septic shock and severe sepsis. Acute septic shock syndrome occurs suddenly and is common in meningococcemia, whereas severe sepsis is characterized by signs of systemic inflammation and organ dysfunction, including abnormalities in body temperature, heart rate, respiratory rate, and leukocyte count, elevated liver enzymes, and altered cerebral function. Severe sepsis runs a protracted course over several weeks, and patients succumb to the disease slowly, and severe sepsis shows only minimal signs of inflammation or necrosis [36, 37]. Some patients with severe sepsis may subsequently develop septic shock. Thus, both severe sepsis and acute septic shock are two phases of the same syndrome and may occur in the same patient but at different periods of time suggesting that causative mediators of these two phases of the disease are different. It appears that sepsis is characterized

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nonsurvivors with severe sepsis (288.8 ± 29.1 nmol/l) compared with survivors (468.1 ± 18.6 nmol/l; p