CNDs are a group of disorders that include cardiovascular disease, some cancers (including breast and colorectal), chronic lung diseases and diabetes. This group of disorders causes 60% of the deaths in the world.¹ Chronic low-grade inflammation plays a significant role in the pathological processes involved in the development and progression of this seemingly diverse group of disorders that also includes dementias, insulin resistance and metabolic syndrome.¹ We now know that contracting muscle secretes chemical mediators that effectively combat chronic inflammation and CNDs, whereas inactive muscle does not secrete these protective mediators.¹

This module will review some of the chemical mediators involved in the acute inflammatory process and use that review as a basis for discussing current concepts in chronic inflammation. The source and impact of various inflammatory mediators will be presented and used to show how chronic inflammation is related to obesity and physical inactivity and how it is a significant component in the initiation and propagation of a variety of CNDs. In addition, we will present data that shows exercise and physical activity cause the secretion of chemical mediators that have an anti-inflammatory impact and reduce chronic inflammation as well as the risk of developing a CND.

Acute inflammation due to infection or trauma results in a characteristic response that occurs on local and systemic levels. Inflammation causes the release of a number of chemical messengers, called cytokines, that mediate many of the changes in function that occur. Cytokines are low molecular weight glycoproteins secreted by cells of the immune system during acute inflammation. The majority of cytokines are classified as either interferons or interleukins. Interferons are involved in protection against viral infections and will not be discussed further in this review. Interleukins are produced mainly by macrophages and lymphocytes during an acute inflammatory response. However, we now know that other cells produce physiologically significant amounts of interleukins as well. Interleukins can be pro-inflammatory or anti-inflammatory, depending upon the response elicited in the target cells.

During an acute inflammatory response, the first cytokine to appear systemically is tumor necrosis factor-alpha (TNF-a).¹ This is followed sequentially by the appearance of several other cytokines, including interleukin-1beta (IL-1ß), interleukin-6 (IL-6), interleukin-1 receptor agonist (IL-1ra), and soluble tumor necrosis factor-alpha receptor (sTNF-R).¹ The level of these cytokines increases dramatically during the acute inflammatory phase, and macrophages, mast cells, and lymphocytes are the main source of these chemical mediators. Some of these cytokines have a pro-inflammatory impact (TNF-a and IL-1ß) and are secreted early in the inflammatory process. The secretion of pro-inflammatory cytokines is followed by the secretion of a different group of cytokines that have an anti-inflammatory effect (IL-1ra and sTNF-R) and help bring the acute inflammatory process to resolution.¹

During acute inflammation, some interleukins act locally to attract lymphocytes, neutrophils and monocytes to promote healing; other cytokines act systemically to induce the liver to produce and secrete a number of “acute-phase response” proteins into the blood.^1,2 IL-6 has a direct role in stimulating hepatic production of the acute-phase response proteins.² This group of proteins provides sensitive markers in the blood that indicate the presence of an active inflammatory response. The erythrocyte sedimentation rate (ESR) is a blood test used as a nonspecific indicator of inflammation. An elevated ESR is a positive, nonspecific indicator of inflammation. C-reactive protein is the most well known and characterized acute phase response protein found in the blood and high levels (>3.0 mg/l) have been associated with chronic inflammation and several CNDs.^3,4

Chronic inflammation is no longer defined simply as inflammation lasting longer than two weeks. Chronic low-grade inflammation is now defined as a persistent, two- to threefold increase in the systemic concentration of the pro-inflammatory cytokines involved in the acute inflammatory response.¹ The presence of chronic, low-grade inflammation can be determined with a blood test for C-reactive protein and/or ESR. Plasma levels of TNF-a, IL-1ß, IL-6, IL-1ra, sTNF-R and C-reactive protein increase dramatically during an acute inflammatory response. In the absence of acute inflammation the level of the pro-inflammatory cytokines, TNF-a, IL-6 and C-reactive protein still show a two- to threefold elevation with aging, obesity, smoking, insulin resistance, type 2 diabetes and atherosclerosis.^1,2 This finding indicates that a chronic, low-grade inflammatory state is present and a component of these conditions. The significance of these findings is that elevated levels of IL-6 and TNF-a are associated with an increased risk of myocardial infarction, and an elevation in C-reactive protein is now known to be a stronger predictor of future cardiovascular disease and events than high levels of low-density lipoprotein (LDL) cholesterol.¹

Endocrinology of Adipose Tissue: Impact of Obesity on Inflammation

Adipose tissue is no longer considered to be an inert site for energy storage. Adipose tissue is now known to secrete a number of hormones and cytokines (e.g., leptin and adiponectin) that are involved in the regulation of body weight, insulin sensitivity and fuel oxidation.^5,6 However, many chemical mediators that originate from adipose tissue have an impact on inflammation, clotting, fibrinolysis, insulin resistance, diabetes, atherosclerosis and some cancers.5 Adipokines are cytokines (chemical messengers) that are made and released from adipocytes.

Adipose tissue is a source of many of the cytokines associated with inflammation.⁵ Tumor necrosis factor-a is a pro-inflammatory cytokine secreted by macrophages during acute inflammation. However, adipose tissue is the main source of basal TNF-a levels found in the circulation when acute inflammation is not present.⁷ The plasma level of TNF-a is directly correlated to the level of obesity and insulin resistance in an individual.5 Weight loss has been shown to result in a reduction of the circulating level of TNF-a.⁵ This cytokine has been shown to modify the insulin receptor in a manner that impairs insulin signaling, causing a reduction in glucose uptake and storage. Infusion of TNF-a in normal, healthy volunteers has been shown to induce a temporary state of insulin resistance.¹ As a result, TNF-a is now considered a significant mediator in the development of insulin resistance, metabolic syndrome and type II diabetes.⁶ TNF-a has been shown to have a role in stimulating production of atherosclerotic lesions and high levels are associated with the onset of cachexia (muscle wasting).⁵

During acute inflammation, IL-6 is secreted by macrophages, lymphocytes, fibroblasts and other cells.¹ However, IL-6 is also secreted by adipocytes, making it an adipokine as well.⁵ In non-obese individuals, adipose tissue makes approximately 30% of the IL-6 found in the circulation at rest, with more IL-6 coming from visceral fat than subcutaneous fat.⁶ The level of IL-6 found in the blood is consistently elevated in obese subjects (people with a body mass index >30).⁵ IL-6 is known to cause the liver and adipose tissue to produce acute-phase reactant proteins, so IL-6 is likely to be responsible for the elevated level of C-reactive protein also found in obese subjects.⁵

In healthy, non-obese individuals, the majority of acute-phase reactant proteins (e.g., C-reactive protein) are produced by the liver in response to IL-6 stimulation.⁵ However, in obese individuals, the level of C-reactive protein is elevated and correlated with the level of obesity present.⁵ In contrast to normal weight subjects, the majority of C-reactive protein comes from adipose tissue in obese individuals. Weight loss by hypocaloric diet and/or surgical intervention has been shown to reduce the level of C-reactive protein found in the blood.⁵

The presence of C-reactive protein in the blood is a significant marker that indicates the presence of an inflammatory state, and it’sone of the strongest predictors of future cases of diabetes and cardiovascular disease.⁵ C-reactive protein directly participates in atherogenesis by impairing endothelial cell function and vasomotor tone. In addition, C-reactive protein amplifies the impact of other pro-inflammatory cytokines that suppress fibrinolysis thus promoting thrombus formation.⁵

Obesity increases the risk of developing insulin resistance, type II diabetes, dyslipidemia, hypertension, cardiovascular disease and erectile dysfunction.⁸ Obesity is associated with chronic low-grade inflammation; obese subjects have elevated levels of the pro-inflammatory cytokines TNF-a, IL-6 and C-reactive protein, while weight loss in obese subjects results in a reduction in the circulating level of these same cytokines.^5,6 These pro-inflammatory mediators — TNF-a in particular — are known to cause vascular dysfunction that facilitates and propagates atherosclerotic plaque formation throughout the circulatory system, increasing the risk of dementia, myocardial infarction and cerebrovascular accident.^2,5

Endocrinology of Muscle: Impact of Physical Activity on Inflammation

Skeletal muscle is the largest tissue in the typical, non-obese human body. Although we have known for a long time that skeletal muscle is affected by hormones, we now know this tissue secretes many important hormones and chemical mediators as well.⁹ Working skeletal muscle secretes cytokines referred to as myokines. The list of myokines includes IL-6, IL-8 and IL-15 among others. Some cytokines, such as IL-6, are adipokines and myokines since they can come from both tissues.⁹ Myokines have a role in producing many of the adaptations that occur as a result of acute and chronic exercise.⁹

During an acute bout of exercise, there is a rise in the transcription, translation and circulating level of IL-6 followed by an increase in the level of anti-inflammatory cytokines like IL-1ra and sTNF-R.^2,7,9 IL-6 from working muscle is known to suppress production of TNF-a, a pro-inflammatory cytokine.^2,7 The peak in the circulating level of IL-6 is typically reached at the end of exercise, and cessation of physical activity is followed by a rapid return to the resting level observed before the exercise session. The peak in IL-6 seen with exercise can be 100-fold greater than the amount at rest before exercise.⁹ The rise in IL-6 is a function of exercise duration, intensity, the size of the working muscle mass, and the endurance capacity.⁷ Type I and type II muscle fibers contribute to the increase in IL-6, and the capacity to secrete IL-6 is not lost in the elderly.^9,10 The rise in IL-6 occurs with or without the occurrence of muscle damage from the physical activity. IL-6 has been shown to increase fatty acid oxidation in muscle and to increase glucose uptake by increasing the insertion of GLUT4 receptors into the cell membrane of muscle. In adipose tissue IL-6 has been shown to increase lipolysis.^7,9

Chronic physical training, defined as repeated and systematic participation in acute bouts of exercise, has been shown to lower the resting level of IL-6 found in the circulation.⁹ The decrease in plasma IL-6 occurs with a simultaneous increase in the number of IL-6 receptors found in muscle. This change results in an overall increase in sensitivity to IL-6. Untrained individuals have higher circulating levels of IL-6 and fewer IL-6 receptors, and they appear to be less sensitive to IL-6 than trained individuals. People with type II diabetes and the elderly have IL-6 levels that are two to three times greater than the amount found in healthy, nonelderly individuals. The significance of these findings is that elevated resting levels of IL-6 are associated with chronic inflammation, obesity and a variety of CNDs, but chronic physical training has been shown to lower the resting level of IL-6, reduce chronic inflammation and lower the risk of CNDs.⁹

Cytokine IL-8 acts as a chemotactic agent to attract neutrophils during an acute inflammatory response.⁹ In addition, IL-8 is now known to be secreted by working muscle and to stimulate angiogenesis locally. Strength training has been shown to dramatically increase the amount of IL-15 found in active muscles.⁹ This myokine has been shown to have a local anabolic affect on skeletal muscle by increasing muscle protein synthesis and simultaneously inhibiting protein degradation.^9,11

Physical Activity as an Intervention for Obesity

Physical activity has been shown to reduce total body fat, as well as central abdominal fat, while counteracting the loss of muscle mass typically seen with hypocaloric dieting without exercise.⁸ Meta-analysis has been used to show that in persons with a BMI greater than 25 exercise-induced weight loss is positively correlated to a decrease in total body fat in a dose-dependent manner.⁸ Weight loss in physically active groups (with or without caloric restrictions) tends to be maintained better than weight loss obtained in groups using only hypocaloric diets.⁸ The significance of these findings is that obesity produces a pro-inflammatory state that predisposes the individual to a variety of disorders. Weight loss appears to attenuate the level of chronic inflammation present as well as the risk of developing CNDs. In addition, physical activity has an anti-inflammatory impact that reduces obesity, chronic low-grade inflammation and the risk of these same disorders.

Training for weight reduction should include large doses of moderate-intensity aerobic exercise combined with some strength training.⁸ The training program must be highly individualized with significant consideration for co-morbidities that may have an adverse impact on the exercise capacity and/or manner of exercise utilized. The minimum dose of physical activity required to induce weight loss appears to be about 30 minutes per day, but that amount does not need to be accumulated in a single session. A longer duration will result in a larger reduction in fat with 60 minutes/day suggested for individuals with larger weight loss goals.⁸

Response to Acute Inflammation Versus Physical Activity

Acute inflammation due to infection or trauma results in a characteristic release of cytokines that have a local and systemic impact. This release of cytokines was described earlier and was noted to include the release of TNF-a followed by the sequential appearance of IL-1ß, IL-6, IL-1ra, sTNF-R and C-reactive protein. The level of these pro-inflammatory and anti-inflammatory cytokines increases dramatically during acute inflammation.^1,2

An acute bout of exercise that does not result in tissue injury causes the release of many cytokines that also have local and systemic effects. However, the characteristic release of cytokines in response to exercise is markedly different than the response to infection or trauma. Following an acute bout of exercise, the first cytokine to appear is IL-6, not the pro-inflammatory cytokines TNF-a or IL-1ß.2 In fact there is no systemic increase in the level of TNF-a, IL-1ß or C-reactive protein following acute exercise unless there is muscle damage. The increase in IL-6 with exercise is followed by a characteristic rise in the anti-inflammatory cytokines IL-1ra and sTNF-R.2

The rise in IL-6 with exercise has an anti-inflammatory impact.² This cytokine inhibits the production and release of the pro-inflammatory cytokines TNF-a and IL-1ß. In addition, the exercise-induced increase in IL-6 stimulates the production and release of the anti-inflammatory cytokines IL-ra and sTNF-R.⁷ These two cytokines inhibit signal transduction through the IL-1 and TNF receptors, respectively, further blocking the inflammatory impact of any IL-1ß and/or TNF-a in the system. A study was performed to evaluate the anti-inflammatory impact of exercise using a low dose of Escherichia coli endotoxin. In physically inactive subjects, injection of the endotoxin induced a two- to threefold increase in the plasma level of TNF-a.² A second group of subjects rode a bicycle ergometer for 2.5 hours prior to injection of the endotoxin. These subjects had no increase in TNF-a following endotoxin injection, suggesting that exercise suppressed the rise in TNF-a and the inflammatory response.²

Chronic physical training is known to be associated with a reduced risk of all-cause mortality independent of any change in BMI.¹² Physical inactivity is now considered to be a stronger predictor than hypertension, hyperlipidemia, diabetes and obesity for all-cause mortality.¹² Cross-sectional studies have shown a strong association between the level of physical inactivity and the amount of low-grade chronic inflammation found in young and elderly subjects.¹

Biomarkers of Inflammation Related to Chronic Noncommunicable Diseases: IL-6

High resting levels of IL-6 are now considered to be equivalent to traditional risk factors (e.g. hypercholesterolemia and hypertension) in terms of predicting future risk of cardiovascular disease and events. A high resting level of IL-6 is strongly associated with physical inactivity.¹³ In a research study, 41 sedentary subjects participated in a moderate-intensity exercise intervention for 24 weeks.¹³ The study measured baseline levels of IL-6 before, during and after the intervention. The 24-week intervention was followed by a two-week detraining period. The level of IL-6 did not change in the control group during the study. However, the resting level of IL-6 was significantly decreased from baseline at 12 weeks and 24 weeks in the exercise group. There was a strong positive correlation between the resting level of IL-6 at the start of the study and the magnitude of the decrease in IL-6 with chronic physical training (i.e., subjects with the highest resting levels of IL-6 at the start had the largest drop in the level of IL-6 at rest after training). Two weeks of physical inactivity in these same subjects resulted in a significant increase in the resting level of IL-6 with some subjects reverting to the baseline level of IL-6 seen before the 24-week exercise intervention.¹³

Chronic endurance (aerobic) training has been shown to lower the resting level of IL-6 found in the blood and simultaneously induce an increase in the expression of IL-6 receptors found in muscle.⁹ The impact of these changes is to increase the sensitivity of muscle to the lower level of IL-6 in the blood. As noted previously, a high resting level of IL-6 is predictive of future cardiovascular disease, so the overall impact of chronic endurance training is to lower the resting level of IL-6 and the risk of future cardiovascular events.

Biomarkers of Inflammation related to Chronic Noncommunicable Diseases: C-Reactive Protein

An elevated level of C-reactive protein in the blood is now considered to be a more powerful predictor of future cardiovascular events, including myocardial infarction and cerebrovascular accident, than a high level of LDL cholesterol in apparently healthy males and females.¹⁴ This biomarker is also considered to be a significant independent predictor of hypertension and diabetes.¹⁵ A study showed that while the level of C-reactive protein was marginally correlated to the level of LDL cholesterol, the level of each was highly correlated to the incidence of future cardiovascular events.¹⁴ Each marker appeared to identify a different group of individuals at risk for cardiovascular disease.

Statins are a class of drugs used to lower the level of LDL cholesterol and thus reduce the risk of cardiovascular disease.¹⁶ Statins are now known to lower LDL cholesterol and simultaneously reduce the level of C-reactive protein, indicating a decrease in the level of chronic inflammation present. Patients with a low level of C-reactive protein after statin therapy have been shown to have better clinical outcomes than patients with an elevated level of C-reactive protein regardless of the level of LDL cholesterol.¹⁶ Aspirin has been shown to reduce inflammation and lower C-reactive protein levels as well.¹⁷

In children and young adults, the level of C-reactive protein found in males and females has been shown to be inversely related to the level of fitness.¹⁸ In addition, C-reactive protein levels have been found to be inversely associated with aerobic fitness across all levels of fitness in adult males.¹⁹ Additional findings in the study demonstrated that in overweight and obese individuals the level of C-reactive protein found was inversely related to the level of aerobic fitness measured.¹⁹ A study using patients in a formal, three-month-long, phase II cardiac rehabilitation program showed that these subjects experienced a significant reduction in the level of C-reactive protein with training that was independent of concomitant statin therapy or any weight loss that occurred during cardiac rehabilitation.²⁰ In a separate study of 14 physically active healthy adults, the level of C-reactive protein was measured before and after training for a marathon.²¹ At the start of the training period, the subjects were running an average of 31 km per week. After nine months of training, the subjects were running an average of 53 km per week. Even though the subjects were physically active at the start of the intense, nine-month aerobic training program, the group still experienced a 31% decrease in the circulating level of C-reactive protein, suggesting that regular physical activity has an anti-inflammatory impact.²¹

The impact of exercise on C-reactive protein levels is not limited to aerobic exercise. Longitudinal studies have shown that 12 weeks of resistance exercise and aerobic training in young and old physically inactive subjects reduced the level of C-reactive protein present.²² The decrease in C-reactive protein observed following training resulted in a resting level of C-reactive protein that was comparable to the amount found in the physically active control subjects.²² Twelve weeks of resistance training has also been shown to decrease C-reactive protein levels in obese female subjects even when there was no change in the body fat.²³

Summary of Physical Activity Versus Chronic Inflammation

Chronic inflammation is no longer simply considered to be acute inflammation that has lasted longer than two weeks. Instead, chronic inflammation is now considered to be a state in which pro-inflammatory cytokines are two to three times above the level considered to be normal. Blood tests for the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) can be used to measure the level of chronic inflammation present. Obesity and physical inactivity produce a state on chronic low-grade inflammation, and these conditions are strongly associated with an elevation in ESR and/or C-reactive protein. Unfortunately, chronic inflammation plays a significant role in the pathological processes involved in the development and progression of chronic noncommunicable diseases. This seemingly diverse group of disorders includes cardiovascular disease, breast cancer, colorectal cancer, some forms of dementia, chronic lung diseases, insulin resistance and diabetes. This group of disorders causes 60% of the deaths in the world.¹ Chronic aerobic exercise and resistance training have been shown to produce an anti-inflammatory state that reduces chronic inflammation as well as decreasing the risk and impact of developing a CND.

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