Exercise and cellular innate immune function : Medicine & Science in Sports & Exercise

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Basic Sciences: Review

Exercise and cellular innate immune function

WOODS, JEFFREY A.; DAVIS, J. MARK; SMITH, JOHN A.; NIEMAN, DAVID C.

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Medicine & Science in Sports & Exercise: January 1999 - Volume 31 - Issue 1 - p 57-66
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Abstract

Epidemiological evidence has revealed an inverse relationship such that moderate to high levels of physical activity or fitness is associated with decreased incidence and/or mortality rates for various cancers (93,103). In addition, several studies have demonstrated that regular moderate physical activity may lead to lowered susceptibility to viral and bacterial infections (65). On the contrary, heavy training or competition may lead to elevated risk (64,86). Experimental studies performed in animals suggest that chronic exercise, especially when performed before tumorigenesis, can retard, delay, or prevent the incidence, progression, or spread of experimental tumors (23,93,105). Moreover, an exercise-induced protective effect has been observed in animal models of infection (16,17); however, this is clearly dependent on the exercise dosage and the infectious disease model (15,17,22,48).

Exercise and physical activity may contribute to alterations in cancer and infectious disease incidence and progression in many ways. One such way is through modulation of the immune system (12). Indeed, it is thought that other stressors (i.e., bereavement, footshock) affect cancer and infectious disease incidence by altering the immune system (7,90). The working theory in the developing field of exercise immunology is the "Inverted J Hypothesis" (Fig. 1). It is hypothesized that there exists a dosage of exercise/physical activity that results in enhanced immune function and reduced cancer and infectious disease incidence. On the other hand, exhaustive exercise, overtraining, or intense competition may lead to immunosuppression and elevated risk for infectious diseases and perhaps cancer. Although the epidemiological data regarding disease appear to support the theory, it remains to be seen whether exercise-induced changes in immune function are responsible.

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Figure 1:
The "Inverted J Hypothesis."

The purpose of this review is to 1) delineate the biological role of cells of the nonspecific (innate) immune system (i.e., macrophages [Mφ], neutrophils [PMN], and natural killer [NK] cells) in infection and cancer; 2) present current information regarding the effects of acute and chronic exercise on the quantification and functional activities of these cells; and 3) to discuss potential mechanisms as to how exercise affects these cells and briefly describe how these changes may potentially affect susceptibility to infection and cancer.

Biological role of cellular innate immunity in infection and cancer. Mφ, PMN, and NK cells constitute a cellular first line of defense against infection and cancer. These cells, unlike cytolytic T lymphocytes, are capable of lysing tumor and virally infected cells without prior exposure. In general, these cells express little cytolytic activity unless recruited or activated by any one of a number of molecules including chemotactic factors (i.e., interleukin-8, C3a) and/or cytokines (i.e., interferon-γ [IFN-γ], interleukin-2, interleukin-12). Upon activation, these cells express potent cytolytic ability mediated by diverse mechanisms such as delivery of TNF-α, nitric oxide, perforin, and cytotoxic granules to susceptible target cells. In addition to their cytolytic function, Mφ and PMN can also phagocytize and clear extracellular bacteria.

Mφ are a first line of defense against microbial invaders and malignancies by nature of their phagocytic, cytotoxic, and intracellular killing capacities (1). They are ubiquitously located throughout the body and are involved in the initiation of immune responses by acting as inflammatory and antigen-presenting cells (18,40). Once established in the tissues, Mφ can exist in a number of functional states dependent on the milieu of stimulatory and inhibitory signals. In humans, monocytes (Mo) constitute a relatively immature form of Mφ available in small numbers in peripheral blood. Because of the fact that tissue Mφ are relatively inaccessible in humans, animal models (utilizing peritoneal Mφ) have been used to study the effects of exercise.

In the peritoneum, resident Mφ are cells that have low functional activity (i.e., quiescent or resting). Inflammatory agents (i.e., thioglycollate [TG]) can elicit Mφ to the peritoneum increasing cell yield and their responsiveness to priming signals (i.e., IFN-γ). IFN-γ, a cytokine produced by activated T cells and NK cells, primes Mφ for antitumor and microbicidal activity (by increasing their sensitivity to lipopolysaccharide [LPS]) and upregulates reactive oxygen and nitrogen production, Fc receptors, and major histocompatibility complex II (MHC II) expression (81). In addition to the priming signal, optimal Mφ activation for complex functions like antitumor and microbicidal activity requires the presence of another signal (i.e., trigger signal). For instance, LPS can trigger full tumoricidal and bactericidal activity (18,40), and PMA or opsonized zymosan can trigger increased levels of superoxide (O2) and H2O2 production (18,20). It is important to understand how exercise affects the transition of cells like the Mφ from a resting to a fully activated state.

PMN play an important role in the nonspecific killing of infectious agents, especially bacteria. PMN uptake of pathogens by phagocytosis triggers a series of nonoxygen- and oxygen-dependent processes that damages and ultimately destroys the microbe within the confines of the cell (98). Phagocytosis results in an oxidative burst, which involves the generation of cytotoxic reactive oxygen species (ROS), and degranulation, which involves release of degradative enzymes into the phagocytic vesical that contains the microbe. This creates an extremely hostile environment that leads to quick killing and degradation (102). However, PMN have also been implicated in the pathology of various inflammatory diseases by release of their toxic products into the extracellular milieu. PMN generally constitute about 60% of circulating leukocytes, thus making them readily accessible to experimental investigation in humans. PMN are the first immune cells to be recruited to sites of infection or inflammation. Although complex and not completely understood, the orchestrated sequence of events that occurs during the PMN response to an infectious episode has been well characterized (98). These events include endothelial adherence, diapedesis, chemotaxis and migration, and phagocytosis. As most of these responses can be measured in vitro, it is not surprising that investigators interested in the link between exercise and infection have measured how these functions are affected acutely by single episodes of exercise and chronically by training. Assays of PMN function involve isolation of the cells from a blood sample and measurement of a functional response in vitro with either unstimulated or stimulated PMN. Stimuli include particles that mimic bacteria and chemotactic peptides or nonphysiological agents that activate biochemical cascades.

NK cells consist of a subset of large granular lymphocytes that exhibit a high ratio of cytoplasm to nucleus and a remarkable capacity to exhibit spontaneous cytotoxic activity against a wide variety of virally infected and tumor cells (42,53,114). In initial studies, NK cells were found to lack most of the markers and properties of T and B cells (42). Over time, NK cells were found to represent a third and distinct population of lymphocytes (about 10-15% in human peripheral blood) in addition to T and B lymphocytes, expressing a characteristic set of markers (CD3, CD2+, CD16+, and CD56+) (113). Much of the work on NK cells has focused on their ability to lyse target cells that have undergone malignant transformation (43,108). Indeed, the "gold standard" measure for NK cell activity (NKCA) has been the chromium release assay, a 4-h assay using cultured tumor cells labeled with radioactive chromium as targets and mononuclear cells isolated from the blood as effectors (14,113). Unlike T cells, NK cells lyse target cells without any apparent previous sensitization and do not require the expression of the MHC on target cells. The basis for target cell recognition by NK cells is still not entirely clear, but they are capable of distinguishing and sparing most normal tissue cells (37,53). Each NK cell can kill an average of two or three target cells, although about 15% of activated NK cells undergo apoptosis as they engage in target cell lysis (104). Most NKCA is mediated through a binding process that involves a pore-forming protein, perforin, and a battery of serine proteases that trigger an endogenous pathway of programmed target cell death (107). There is growing evidence that NKCA is reduced in certain cancer patients (13,114,115). NK cells also respond rapidly to viral challenge, mounting a proliferative and cytolytic response days before the more specific T-cell response can be generated (25,108). Susceptibility to various types of infections has been described in experimental animals depleted of NK cells and in patients with defective NK cell function (45,53). Cytokines, especially interferon-α, interleukin-2 (IL-2), and IL-12, are efficient activators of NKCA (6,89).

It should be pointed out that although cells of the innate immune system are important initial effector cells, they are also under regulatory influence of other cells (including T and B lymphocytes) and hormones produced by the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. Therefore, they cannot simply be viewed as individual cells but as part of a complex network of cells and tissues that communicate in many different ways in an attempt to elicit an appropriate host response to cancer or infection. Indeed, it may well be that stressors, including exercise, exert their regulatory influence over these cells by activating the SNS, HPA axis, or by influencing other tissues or cells (21). For example, it is known that exercise results in damage to muscle tissue; this may result in an acute phase response initiated by infiltrating inflammatory cells (73). Other potential mechanisms responsible for altered innate immune cell function include elevated body temperature (11), availability of energy sources (80), and exercise-induced systemic endotoxemia (10). All of these potential mechanisms of influence are speculative and require further testing before definitive conclusions as to their effects on cells of the innate immune system can be made.

Exercise and macrophage function. Exercise stress, unlike other stressors (82), appears to have a stimulatory effect on many functions of Mo and Mφ; however, this may be site specific. Exercise-induced augmentation of peritoneal Mφ phagocytosis, metabolic and lysosomal enzyme activities, chemotaxis, and oxidative burst have been documented. However, not all measures are positively affected. Acute strenuous exercise appears to be the most potent modulator, but moderate bouts affect these cells as well. There are very few data regarding the effects of chronically performed exercise on Mφ function. Pressing questions remain as to the physiological significance of exercise-induced changes in Mo/Mφ function. Furthermore, the mechanisms responsible for the apparent stimulatory effect of exercise on Mφ remain to be resolved.

Acute exercise responses. Numerous studies suggest that exercise training has no effect on Mo numbers in peripheral blood of resting subjects (119). However, acute exercise, irrespective of intensity or duration, causes a transient monocytosis (119) most likely because of demargination caused by altered vascular hemodynamics or changes in monocyte-endothelial cell interactions mediated by catecholamines. There may be exercise intensity/duration-dependent changes in subpopulations of Mo such that mature Mo may migrate out of the vasculature after long-duration exercise (34). Quantification of tissue Mφ has not been studied extensively; however, we have found that exhaustive exercise performed during inflammation dramatically decreased the number of elicited Mφ (118). Exercise-induced changes in the number and types of cells recruited to sites of inflammation or tumorigenesis may be more physiologically relevant than transient changes in blood Mo and warrants further investigation.

Both acute and moderate and exhaustive exercise have been shown by several groups, and in several different species (humans, mice, and guinea pigs), to enhance a variety of Mφ capacities including chemotaxis (31,60,75,79), adherence (75,79), and phagocytic (24,28,29,60,75,77,78,79) and cytotoxic (23,117,118) activity. One group has attempted to delineate the mechanism responsible for the exercise-induced increases in chemotaxis (79) and phagocytosis (32). Their circumstantial evidence points to a hormonal influence perhaps mediated by corticosterone or prolactin and thyroxine, in the case of chemotaxis and phagocytosis, respectively. They have shown that incubation of Mφ from control animals with plasma from exercised animals stimulates chemotaxis and phagocytosis to similar levels seen in Mφ taken from exercised animals (32,79). In addition, incubation of Mφ with physiological levels (i.e., plasma levels attained during exercise) of corticosterone, prolactin, or thyroxine could stimulate chemotaxis or phagocytosis. Unfortunately, they have failed to definitively define their role by pharmacological or surgical manipulation in vivo.

Woods and colleagues (117,118) have shown that both moderate and exhaustive treadmill running over periods of 3-7 d increases the antitumor activity of TG-elicited and Propionibacterium acnes-activated murine peritoneal Mφ. These effects were not due to altered numbers of Mφ in the assay system but were attributable, in part, to increased production of TNF-α from TG-elicited Mφ and increased NO production from P. acnes-activated Mφ. In a similar study, Lotzerich et al. (1990) found that the cytostatic, but not antibody dependent cytolytic, activity of murine peritoneal Mφ was enhanced after a single exhaustive running session (54). It is important to note that the results of the two studies are consistent despite the fact that different strains of mice, tumor targets, and exercise protocols were used. The role these exercise-induced changes in Mφ antitumor activity play in affecting tumor incidence and progression in vivo is unclear. Despite an exercise-induced increase in intratumoral Mφ number and activity, Woods et al. (120) found no changes in tumor incidence or progression. However, exercise was performed during (not before) tumorigenesis. In addition, the short duration of the study, the large dose of tumor cells transplanted, and the weakly immunogenic nature of the tumor may all have contributed to the lack of an effect. Indeed, recent research using an experimental tumor metastasis model in mice shows that the number of lung tumor metastases resulting from an intravenous injection of B16 melanoma cells was decreased after an acute bout of treadmill exercise. This was associated with an enhancement of antitumor cytotoxicity by alveolar Mφ (23).

In contrast to the exercise-induced augmentation of several Mφ functions, recent data from Woods et al. (121) have demonstrated that 7 d of both moderate and exhaustive exercise reduced the induction of MHC II on Mφ activated by suboptimal doses of P. acnes. At optimal doses of P. acnes, only exhaustive exercise suppressed MHC II induction. This effect may be detrimental to the Mφ ability to present antigen to T lymphocytes. The physiological consequences of these exercise-induced changes in Mφ MHC II expression are unknown, but it must be cautioned that MHC II expression is one capacity among several (i.e., phagocytosis, phagolysosome fusion, peptide coupling to MHC II) that are required for optimal antigen presentation. However, Davis and colleagues also have evidence consistent with the notion that stressful exercise may decrease Mφ antiviral function and thereby increase susceptibility to infection. They recently reported that lung Mφ taken from mice exercised to fatigue had a greater degree of viral replication (plaque titration assay) and IFN-β expression after herpes simplex virus type I (HSV-1) infection in culture than Mφ taken from sedentary mice (49). They also found that mice exercised to fatigue (but not moderately) had reduced intrinsic alveolar Mφ antiviral resistance (as measured by cytopathic effect) at several time points postexercise and experienced greater morbidity and mortality in response to HSV-1 infection (22). A follow-up experiment designed to determine the role of stress hormones in this response suggested that the reduction in alveolar Mφ antiviral resistance was likely related to increased release of adrenal catecholamines but not corticosterone (48).

There is some evidence that exercise itself increases production of cytokines but may inhibit the production of cytokines in response to inflammatory stimuli like LPS or P. acnes. In humans, the most reliable and quantitatively largest exercise-induced increase in plasma cytokine level has been observed with interleukin-6 (IL-6) (112). Ullum et al. (111) found that 1 h of bicycling at 75% V˙O2max increased plasma levels of IL-6 but not IL-1α, IL-1β, and TNF-α. IL-6 mRNA was not increased in blood mononuclear cells from these same subjects. In contrast, in animal models where cytokines are induced by LPS (2) or a combination of P. acnes and LPS (44), prior exercise has been shown to inhibit cytokine induction. For example, Bagby et al. (2) found that prior exhaustive exercise in rats profoundly reduced the ability of LPS to stimulate TNF-α levels in plasma. It is not clear as to the cellular or tissue source of the cytokines, but many of the cytokines altered by exercise can be produced by cells of the Mo/Mφ lineage. In conclusion, it appears that the modulatory effect of exercise on the Mo or Mφ is dependent on the parameter being measured, the timing, intensity, and duration of the exercise, and the dosage of immunomodulator being utilized.

Chronic exercise responses. There are very few studies on the effects of chronic exercise on the functional abilities of Mφ. Most of the studies that have been done have utilized acute exercise bouts. However, exercise of longer periods of time may result in phenotypically or functionally different populations of Mφ. Mahan et al. (59) found that splenic Mφ from control sedentary and exhaustively exercised mice, when added to splenocytes, equally reduced proliferation in response to concanavalin A (Con A). In contrast, splenic Mφ from 13-wk exercise-trained animals enhanced splenocyte proliferative responses to Con A. This effect was not mediated by a reduction in prostaglandin E2 (which inhibits proliferation) in that indomethacin was unable to block the exercise training induced enhancement. Twenty-five days of treadmill running (15 m·min−1, 30 m·d−1) resulted in increased metabolic and lysosomal enzyme activities and enhanced phagocytic activity in murine peritoneal Mφ (28). In general, others have found that the acute exercise-induced effects seen in various peritoneal Mφ functions are somewhat attenuated after exercise training of 30 or less days' duration but are still significantly different from sedentary control animals (28,75,77). This suggests that acute exercise (especially novel strenuous exercise) may be the most potent stimulus for altering peritoneal Mφ activity and that chronic training may cause adaptations that diminish the acute exercise response. Therefore, based on these data on Mo and Mφ, the global statement that stress causes immunosuppression of all cells of the immune system is no longer valid.

Exercise and neutrophil function. The aim of this section of the review is to summarize how exercise affects neutrophil function in human subjects in response to acute and chronic exercise. The reader should consult a more detailed recent review for further information (102). At present, a straightforward interpretation of the literature on exercise and PMN function is not possible because of the wide diversity of exercise protocols and functional assays used. Although conflicting results have been found, PMN responses to a single episode of exercise are, in general, intensity dependent. Although exercise at low to moderate intensity enhances some aspects of PMN function, maximal exercise is generally suppressive. Irrespective of these trends, the release of elastase (a marker of PMN degranulation) into the circulation, which occurs during both moderate and intense exercise, indicates that exercise has affected the PMN population.

Compared with untrained individuals, endurance athletes show significant decrements in some PMN functions. These responses fit in with the epidemiological data that show that endurance athletes are more susceptible to certain infections than less active individuals. However, caution should be employed when interpreting the literature. Given the complexity and redundancy of the immune system, it is virtually impossible to establish a direct "cause-and-effect" link between changes in the incidence of infection and PMN function, especially in human studies. Furthermore, large fluctuations in some PMN functional activities may not be biologically significant. Only after these functions fall below a critical (as yet unknown), threshold might pathological consequences occur. Given these caveats, however, changes in certain PMN functions may be useful indicators of stress and immunosuppression. That is, a fall in certain functions may be indicative of distress such as overtraining. Should such a link be established, assays of PMN function may be used as part of a diagnostic set of variables that are used to monitor the health of the intensely training athlete. This has important practical consequences because many assays of PMN function are fairly easy to perform and require small samples of blood.

Acute exercise responses. Acute exercise induces a profound leukocytosis that includes an increase in the number of PMN. PMN counts are increased during and immediately after exercise of a wide range of intensities and durations, most probably as a consequence of demargination mediated by altered hemodynamics and catecholamines (19,94). A second delayed neutrophilia occurs several hours postexercise as a result of mobilization from bone marrow in response to elevated cortisol levels or humoral signals (19,94). The magnitude of the neutrophilia is exercise intensity and duration dependent (19,94).

Contrasting responses in PMN function have been reported after moderate exercise. The findings so far suggest that although some functional responses are enhanced, others are not affected significantly. Although some studies show that the capacity of PMN to generate microbicidal ROS is enhanced after exercise (27,100,101), others have reported a temporary suppression (55,88). The same trends have been found in microbial killing assays. Although one study found that a short period of running at 80% of maximum heart rate (HR) increased the capacity of PMN to kill fungi (89), another found no significant changes after 1 h of cycling at 50% V˙O2max(76). Chemotactic and phagocytic functions are also boosted after moderate exercise (76). Others have also reported that the expression of certain cell surface molecules increases after exercise (51,101); this provides further evidence that PMN are affected by moderate exercise.

Responses to single episodes of exercise are generally measured immediately after the exercise test is completed and compared with the preexercise (resting) response. Given that there may be a considerable lag time between completion of the exercise test and a functional response, it is not surprising that conflicting reports have appeared. These conflicts could be resolved by taking multiple postexercise measurements for up to 24 h and controlling for the influence of pulsatile fluctuations over that time course (99,101). Degranulation should also be assessed because the net response may represent a balance between primed and activated PMN (101). A recent report suggests that intermittent low intensity exercise over a large part of the day enhances the capacity of PMN to generate ROS (116). Therefore, previous exercise activity may also influence the results and explain discrepancies. In addition, duration, exercise type, and physical fitness vary quite markedly between studies.

In contrast to moderate exercise, the reported responses to maximal exercise are more consistent. With the exception of phagocytosis and degranulation, most PMN functions fall significantly after an episode of maximal exercise. Our group and others have shown that the capacity of PMN to generate ROS in response to stimulation in vitro is suppressed immediately after exercise (35-37,50,100). Several groups have shown that progressive exercise to exhaustion increases phagocytic and opsonization capacity (38,39,52,91). Because evidence of degranulation (i.e., elastase activity increases in plasma) has been found after maximal and prolonged exercise (26,36,50), and given that degranulation is indicative of PMN activation in vivo, it is possible that activated cells will not respond to secondary stimulation until a certain recovery time has elapsed. We have called this phenomenon the "postexercise refractory period." Several studies have shown a suppression in the oxidative burst immediately after exercise (38,39,88). Because the magnitude of degranulation is proportional to run distance (41), it is likely that the majority of the PMN population is in an unresponsive state after maximal exercise. This postexercise refractory period may create a window of opportunity for opportunistic infections to become established. As discussed under moderate exercise, standardization of exercise protocols and assays as well as an extended sampling time course may resolve present conflicts.

One group has examined PMN function in response to exercise in tissue other than blood. Muns (61) found that a 20-km race resulted in a 1.5- to 2-fold increase in the number of PMN obtained by nasal lavage immediately and one day after the race. They also found that the in vitro chemotactic activity in PMN obtained from nasal lavage was increased after a marathon run (62). Interestingly, the phagocytic activity of these PMN (including the percentage of phagocytizing cells and the ingestion on a per cell basis) was reduced approximately in half for up to 1 d after (61). These findings suggest that strenuous exercise impairs upper airway antimicrobial defense and may contribute to the higher incidence of upper respiratory tract infections in athletes.

Chronic exercise responses. This section will focus on comparisons between endurance athletes and individuals who are considered to be fairly inactive (untrained). There are few studies on team sports or power athletes. The intensity, duration, type, and frequency of the training program must also be carefully considered as should the stage. One problem in interpreting some reports is that training programs are poorly described and lack details on the aspects described above. Despite these problems, training effects are more consistent than responses reported after acute exercise. Although studies are few and training protocols varied, it appears that moderate training results in an increase in resting blood PMN count, whereas strenuous training may lead to a reduction in blood PMN number. We have consistently found that endurance training reduces the capacity of PMN to produce ROS in response to stimulation in vitro(87,100). Others have reported that ROS generation (39) and bacterial killing capacity (52) are also much lower during periods of intense training. In contrast, PMN from basketball players show higher chemotactic and phagocytic activities compared with cells from untrained people (8,9). The overall stress level may explain the differences found between endurance athletes and basketball players. This would be a fruitful area for future investigation.

The work shows that exercise does cause functional alterations in neutrophil function. The physiological and clinical significance of these responses are at present unknown. The situation is further complicated by the fact that reference ranges for these functions have not been established. Despite these caveats, the overall trends fit in with the epidemiological evidence that suggests that although moderate exercise enhances PMN function intense physical activity is detrimental.

Exercise and natural killer cell function. Because of the importance of NK cells in functioning as an early defense line against viruses, exercise immunologists have been eager to study the response of these cells to exercise stress. Several epidemiological studies suggest that heavy exertion is related to an increased risk of upper respiratory tract infection, and the response of NK cells has been evaluated as one potential link (64,65,86).

Acute exercise responses. Of all lymphocyte subsets, NK cells are most responsive to exercise stress. It is typical for NK cell number in peripheral blood to increase 150-300% immediately after short-term (<60 min), high-intensity exercise and to contribute substantially to the overall lymphocytosis (30,33,66,84,85,95,110). NK cells have a high density of β2-adrenergic receptors, explaining why blood counts increase strongly during high-intensity exercise when concentrations of epinephrine are high (47,67). Epinephrine, via β2-adrenergic receptors, can induce recruitment of NK cells from the marginating pool in blood vessels to the circulating pool, by changing the adhesive interactions between NK cells and endothelial cells (4). The postexercise increase in NK cells is transient, however, and within 30 min, NK cells exit the circulation in large numbers, probably under the influence of cortisol (67,106). It should be noted that immediately after long-term (>90-min duration), high-intensity exercise, little increase in blood NK cell counts are seen, most likely because of high plasma cortisol levels, which counteract epinephrine-induced NK cell recruitment (68,72).

Investigators have consistently reported that immediately after high-intensity exercise of 1 h or less duration, NKCA is increased by 40-100% before falling 25-40% below preexercise levels by 1 h and 2 h of recovery (30,67,84,85,95,110). Although most researchers agree that the immediate postexercise increase in NKCA is due to the recruitment of NK cells into the circulation, they tend to disagree on the reasons for the transient NKCA decrease during recovery. Some researchers reason that the drop in NKCA is related to numerical shifts in NK cells (30,67,95), whereas others report that prostaglandins from activated monocytes and neutrophils (84,85) suppress the ability of NK cells to function appropriately.

Immediately after long-duration, high-intensity exercise bouts, no increase in NKCA is seen, and the drop in NKCA during recovery is greater and more sustained than with bouts lasting less than 1 h (5,56,57,67,68,72,84,92,96)(Fig. 2). Indomethacin, vitamin C, and carbohydrate supplementation have been shown to have no significant effect in attenuating the drop in NKCA after prolonged heavy exertion, whereas adjustment for changes in NK cell concentration completely eliminates the decline (68,71,72). Even though the per-NK cell function is not impaired after exercise, the loss of NK cells from the circulation means that the blood compartment as a whole suffers a transient decrease in NKCA capacity. Unresolved are issues involving destination sites for NK cell trafficking activity, whether blood compartment NK cells reflect the NKCA capacity of other lymphoid sites, and overall effects on host protection (67,68,85).

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Figure 2:
The decrease in natural killer cell activity (percent change in total lytic unit from prerun levels) is greater and more sustained following 2.5-3 h of intensive running (∼76% V˙O2max) compared with 45 min of intensive running (∼80% V˙O2max). Data represent studies on 62 marathon runners (5,68,69) and 10 middle-distance runners (64). References: 5. Berk, L. S., D. C. Nieman, W. S. Youngberg, et al. The effect of long endurance running on natural killer cells in marathoners. Med. Sci. Sports Exerc. 22:207-212, 1990; 64. Nieman, D. C., L. M. Johanssen, J. W. Lee, and K. Arabatzis. Infectious episodes in runners before and after the Los Angeles Marathon. J. Sports Med. Phys. Fitness 30:316-328, 1990; 68. Nieman, D. C., J. C. Ahle, D. A. Henson, et al. Indomethacin does not alter natural killer cell response to 2.5 h of running. J. Appl. Physiol. 79:748-755, 1995; 69. Nieman, D. C., K. S. Buckley, D. A. Henson, et al. Immune function in marathon runners versus sedentary controls. Med. Sci. Sports Exerc. 27:986-992, 1995.

Both in vitro and in vivo studies have failed to demonstrate that epinephrine has an effect on NKCA beyond its effect on redistributing mononuclear cell subsets (47). Short-term (<5 h) infusion studies have failed to demonstrate that cortisol has any effect on NKCA (106), and in vitro studies suggest that unless cells are preincubated with cortisol for extended time periods (>20 h), no effect on NKCA can be measured (63,74).

Chronic exercise responses. Although not entirely consistent (97), several cross-sectional studies support the finding of enhanced NKCA in athletes when compared with nonathletes, in both younger and older groups (66,69,83,109). Animal data have systematically shown that NKCA is elevated in trained versus untrained mice and rats (46,58). Several studies utilizing moderate endurance training regimens over 8-15 wk, however, have reported no significant elevation in NKCA among trained versus untrained humans (3,65,66,70). Together, these data imply that endurance exercise may have to be intensive and prolonged (i.e., at athletic levels) before NKCA is chronically elevated in humans.

The repetitive but transient decrements in NKCA after each bout of heavy exertion (most likely because of hormone-induced NK cell trafficking) balanced against the potential increase in resting NKCA presents a complex and interesting enigma that will require further research before meaningful clinical applications can be formulated.

Conclusions/future directions. The effects of exercise on the number, functions, and characteristics of cells of the innate immune system are complex and are dependent several factors including 1) the cell function or characteristic being analyzed; 2) the intensity, duration, and chronicity of exercise; 3) the timing of measurement in relation to the exercise bout; 4) the dose and type of immunomodulator used to stimulate the cell in vitro or in vivo; and 5) the site of cellular origin. NK cell and PMN function may be suppressed immediately and several hours after acute exercise, especially if intense. In addition, Mφ and PMN in the airways appeared to be suppressed as well. This may contribute to an increased incidence of infection in the postexercise period. On the contrary, many peritoneal Mφ functions are positively affected by both moderate and exhaustive exercise. The physiological significance of these findings is unknown.

Future studies need to pay careful attention to the populations of cells being analyzed. Heterogeneity exists among seemingly homogenous populations of Mφ, PMN, and NK cells, regardless of the tissues where the cells are obtained. For example, analysis of blood Mo function after exercise may be confounded by the fact that subtle shifts in the proportions of immature and mature Mo occur in response to exercise (34). Therefore, changes in cell subpopulations might be misinterpreted as changes in cell function on a per cell basis. Two major hurdles and areas for future work for exercise immunologists are to 1) determine whether the exercise-induced changes in immune function alter incidence or progression of disease and 2) determine the mechanisms as to how exercise alters immune function. Appropriate animal models may be of use in addressing these issues.

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Keywords:

EXERCISE; IMMUNE; MACROPHAGE; NEUTROPHIL; NATURAL KILLER CELL; CANCER; INFECTION

© 1999 Lippincott Williams & Wilkins, Inc.