Download Immune function in sport and exercise

J Appl Physiol 103: 693–699, 2007;
doi:10.1152/japplphysiol.00008.2007.
HIGHLIGHTED TOPIC
Invited Review
Exercise and Inflammation
Immune function in sport and exercise
Michael Gleeson
School of Sport and Exercise Sciences, Loughborough University, Loughborough, United Kingdom
cytokines; leukocytes; infection; inflammation; Toll-like receptors
THE AIM OF THIS REVIEW IS to provide an up-to-date summary of
the known effects of exercise on immune function and infection risk and to point out some of the main flaws of research to
date and challenges for the future. Exercise can have both
positive and negative effects on immune function and susceptibility to minor illnesses. The relationship between exercise
and susceptibility to infection has been modeled in the form of
a “J”-shaped curve (28). This model suggests that, while
engaging in moderate activity may enhance immune function
above sedentary levels, excessive amounts of prolonged, highintensity exercise may impair immune function. Although
there is relatively little evidence available to suggest that there
is any clinically significant difference in immune function
between sedentary and moderately active persons, there is
some fairly convincing epidemiological evidence that moderate habitual physical activity is associated with decreased
infection incidence. For example, it has been reported that the
regular performance of ⬃2 h of moderate exercise per day is
associated with a 29% reduction in risk of picking up upper
respiratory tract infection (URTI) compared with a sedentary
lifestyle (25). In contrast, it has been reported that there is a
100 –500% increase in risk of picking up an infection in the
weeks following a competitive ultra-endurance running event
(30, 35, 36). However, a recent study (7) failed to confirm these
findings in a large cohort of marathon runners: no relation was
found between training volume during 6 mo before a marathon
race and the postrace incidence of self-reported URTI epi-
Address for reprint requests and other correspondence: M. Gleeson, School
of Sport and Exercise Sciences, Loughborough Univ., Loughborough, Leicestershire LE11 3TU, UK (e-mail: [email protected]).
http://www. jap.org
sodes, and there was no difference in infection incidence in the
3 wk after the race compared with before. Of interest though
was the observation that the post-race URTI incidence in
runners without URTI symptoms in the 3 wk preceding the
race was 16% (and not different from prerace URTI incidence),
whereas, in runners who experienced an URTI episode in the 3
wk before the race, 33% experienced an URTI episode after the
race also (7). This suggests that the stress of the exercise may
have allowed a reactivation of the virus responsible for the
prerace infection. Furthermore, in none of these studies were
infections clinically confirmed, so it cannot be ruled out that
some of the reported symptoms (e.g., sore throat) were caused
by noninfectious airway inflammation due to drying of the
mucosal surfaces and/or the inhalation of dry air or pollutants.
Many studies have reported that various immune cell functions are temporarily impaired following acute bouts of prolonged, continuous heavy exercise (24, 28, 33, 38, 43, 45), and
athletes engaged in intensive periods of endurance training
appear to be more susceptible to minor infections. For example, according to some surveys, sore throats and flu-like symptoms are more common in athletes than in the general population, and, once infected, colds may last longer in athletes (18,
30, 34). This is obviously a concern for athletes, as it is
generally recognized that even minor infections can result in a
drop in exercise performance and the ability to sustain heavy
training (40). More severe viral infections can be associated
with the development of persistent fatigue (10). Even so, there
are very few studies that have been able to demonstrate a direct
association between any specific measure of exercise-induced
impaired immune function and increased incidence of clinically confirmed infection.
693
Downloaded from http://jap.physiology.org/ by 10.220.32.247 on May 12, 2017
Gleeson M. Immune function in sport and exercise. J Appl Physiol 103:
693– 699, 2007. doi:10.1152/japplphysiol.00008.2007.—Regular moderate exercise is associated with a reduced incidence of infection compared with a completely
sedentary state. However, prolonged bouts of strenuous exercise cause a temporary
depression of various aspects of immune function (e.g., neutrophil respiratory burst,
lymphocyte proliferation, monocyte antigen presentation) that usually lasts ⬃3–24
h after exercise, depending on the intensity and duration of the exercise bout.
Postexercise immune function dysfunction is most pronounced when the exercise is
continuous, prolonged (⬎1.5 h), of moderate to high intensity (55–75% maximum
O2 uptake), and performed without food intake. Periods of intensified training
(overreaching) lasting 1 wk or more may result in longer lasting immune dysfunction. Although elite athletes are not clinically immune deficient, it is possible that
the combined effects of small changes in several immune parameters may compromise resistance to common minor illnesses, such as upper respiratory tract
infection. However, this may be a small price to pay as the anti-inflammatory
effects of exercise mediated through cytokines and/or downregulation of toll-like
receptor expression are likely mediators of many of the long-term health benefits of
regular exercise.
Invited Review
694
IMMUNE FUNCTION IN SPORT AND EXERCISE
ACUTE EFFECTS OF EXERCISE ON IMMUNE FUNCTION
A single, acute bout of prolonged, strenuous exercise has a
temporary depressive effect on immune function, and, in a few
studies involving rather extreme exercise (marathons and ultramarathons), this has been associated with an increased
incidence of infection in the weeks following the event. For
example, several studies have described a substantially higher
(two- to sixfold) frequency of self-reported symptoms of URTI
in athletes who completed long-distance foot races compared
with control runners who did not compete in the events (30,
34 –36). An acute bout of physical activity is accompanied by
responses that are remarkably similar in many respects to those
induced by infection, sepsis, or trauma (32): there is a substantial increase in the number of circulating leukocytes (mainly
lymphocytes and neutrophils), the magnitude of which is
related to both the intensity and duration of exercise. There are
also increases in the plasma concentrations of various substances that are known to influence leukocyte functions, including inflammatory cytokines, such as TNF-␣, macrophage
inflammatory protein-1, and IL-1␤; anti-inflammatory cytokines IL-6, IL-10, and IL-1-receptor antagonist (IL-1ra); and
acute phase proteins, including C-reactive protein (CRP). The
large increase in plasma IL-6 concentration observed during
exercise can be entirely accounted for by release of this
cytokine from contracting muscle fibers (51). However, IL-6
production by monocytes (49) and IL-2 and IFN-␥ (but not
IL-4) production by T lymphocytes are inhibited during and for
several hours after prolonged exercise (21, 32).
Hormonal changes also occur in response to exercise,
including increases in the plasma concentration of several
hormones [e.g., epinephrine (adrenaline), cortisol, growth hormone, and prolactin] that are known to have immunomodulatory effects. Muscle-derived IL-6 appears to be at least partly
responsible for the elevated secretion of cortisol during prolonged exercise. Infusion of recombinant human IL-6 into
resting humans to mimic the exercise-induced plasma levels of
IL-6 increases plasma cortisol in a similar manner (50). In
contrast, the same recombinant human IL-6 infusion does not
J Appl Physiol • VOL
change plasma catecholamine or insulin levels in resting
healthy young subjects. Therefore, muscle-derived IL-6 may
be partly responsible for the cortisol response to exercise,
whereas other hormonal changes cannot be ascribed to IL-6.
Stimulation of cortisol secretion by IL-6 may be due to an
effect of IL-6 on the hypothalamus, stimulating the release of
ACTH from the anterior pituitary gland, or by a direct effect of
IL-6 on cortisol release from the adrenal glands; evidence for
both mechanisms exists. In addition, it was recently demonstrated that relatively small increases in plasma levels of IL-6
induce the two anti-inflammatory cytokines IL-1ra and IL-10,
together with CRP (50). During exercise, the increase in IL-6
precedes the increase in these two cytokines, arguing circumstantially for muscle-derived IL-6 to be the initiator of this
response.
Whether humoral or cell-mediated immunity will dominate
depends largely on the type of cytokines that are released by
the activated T helper cells. T lymphocytes can be classed as
type 1 or type 2 cells, depending on which cytokines they
predominantly produce. Type 1 T cells produce mainly IFN-␥
and tumor necrosis factor, and their actions activate macrophages and induce killer mechanisms, including T-cytotoxic
cells, thus driving the immune system toward cell-mediated
immune responses, which primarily provide protection against
intracellular pathogens such as viruses. Type 2 cells mainly
produce IL-4, IL-5, IL-10, and IL-13, which are necessary for
promotion of humoral immunity, IgE-mediated allergic reactions, and activation of potentially tissue-damaging eosinophils. IL-4 and IL-13 primarily drive B-cell differentiation to
antibody production, while IL-5 stimulates and primes eosinophils. Together with IL-4, IL-10 (which is also produced by
monocytes and B cells) can inhibit type 1 T-cell cytokine
production. Interestingly, it appears that exercise can influence
the type 1/type 2 cytokine balance.
In accordance with the elevations of circulating IL-6, IL-10,
and IL-1ra, strenuous exercise decreases the percentage of type
1 T cells in the circulation, whereas the percentage of type 2 T
cells does not change (21). Both cortisol and epinephrine
suppress the type 1 T-cell cytokine production, whereas IL-6
directly stimulates type 2 T-cell cytokine production. Another
important action of IL-6 is that it suppresses production of
TNF-␣, which is a potent activator of inflammation (48). As
type 1 T cells promote cell-mediated immune responses, which
primarily provide protection against viruses, exercise, possibly
working through muscle-derived IL-6, may decrease virus
protection in the host and thus may account for why athletes
appear to be more prone to acquire URTI. However, it is very
important to stress that the shift toward type 2 T-cell dominance might be beneficial, because it also suppresses the ability
of the immune system to induce tissue damage and inflammation. Blood markers of inflammation are strongly associated
with cardiovascular and metabolic disease in the middleaged and elderly population, and inflammation has been
implicated in the pathology of several chronic diseases.
Thus elevated systemic levels of IL-6 during and following
exercise could be one of the mechanisms by which regular
exercise provides protection against the development of
chronic diseases (Fig. 1). However, it could be argued that the
relative importance of IL-6 in this context is likely to be rather
small, as significant health benefits of regular exercise are
apparent even when the exercise is of light-moderate intensity
103 • AUGUST 2007 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.32.247 on May 12, 2017
The circulating numbers and functional capacities of leukocytes may be decreased by repeated bouts of intense, prolonged
exercise. The reason is probably related to increased levels of
stress hormones during exercise (26) and entry into the circulation of less mature leukocytes from the bone marrow (13).
Falls in the blood concentration of glutamine have also been
suggested as a possible cause of the immunodepression associated with heavy training, although the evidence for this is less
compelling (13). Also, during exercise, there is an increased
production of reactive oxygen species, and some immune cell
functions can be impaired by an excess of free radicals (31).
During exercise, exposure to airborne pathogens is increased
due to the higher rate and depth of breathing. An increase in
gut permeability may also allow increased entry of gut bacterial endotoxins into the circulation, particularly during prolonged exercise in the heat. Hence the cause of the increased
incidence of infection in athletes is likely to be multifactorial:
a variety of stressors (physical, psychological, or environmental, nutritional) can suppress immune function (13), and these
effects, together with increased exposure to pathogens, can
make the athlete more susceptible to infection.
Invited Review
IMMUNE FUNCTION IN SPORT AND EXERCISE
695
Fig. 1. Possible mechanisms by which exercise increases
susceptibility to infection but reduces inflammation and risk
of developing chronic disease. TLR, Toll-like receptor; TH1,
T helper 1; IL-1ra, IL-1 receptor antagonist. The encircled
minus sign represents an inhibitory action of IL-6 on TNF
production.
J Appl Physiol • VOL
Numerous studies report effects of exercise on functions of
isolated leukocytes when these cells are stimulated in vitro by
added antigens or mitogens. However, it is difficult to extrapolate from the ex vivo stimulated response of isolated cells to
how these same cells would respond in the far more complex
in vivo environment. In addition to the presence of antigens,
leukocyte function is also influenced by endogenous chemicals, including hormones, neurotransmitters, and cytokines,
and the plasma concentration of these may change during
exercise. The pH and temperature of the blood also change
during exercise, but these factors are often ignored in experiments on isolated cell types. Thus separating cells from their
in vivo environment is somewhat artificial and to a large degree
excludes the effects of exercise-induced chemical changes in
the blood that will undoubtedly modify leukocyte function.
The closest one can get to the in vivo condition is by performing measurements on whole blood, in which the proximity
between the leukocytes and the extracellular milieu is retained.
Another limitation in the interpretation of such studies, even
where multiple parameters are assessed, is that presently no
instruments are available to predict the cumulative effects of
several small changes in immune system parameters on host
resistance (19). Furthermore, it should be borne in mind that
only 0.2% of the total leukocyte mass is circulating at any
moment; the remainder is in lymphoid tissue, the bone marrow,
and other tissues. It may thus be more important to assess the
status of leukocytes in the skin, mucosa, and lymph nodes
rather than in the blood.
CHRONIC EFFECTS OF EXERCISE TRAINING
ON IMMUNE FUNCTION
Following an acute bout of exercise, changes in circulating
leukocyte numbers and functions normally return to preexercise values within 3–24 h. Cross-sectional studies that have
compared leukocyte numbers and functions in blood samples
taken from athletes more than 24 h after their last training
session with those of sedentary individuals have generally
reported very few differences. Thus, in the true resting state,
immune function appears to be broadly similar in athletes
compared with nonathletes. There is a weak suggestion of a
slightly elevated NK cell count and cytolytic action in trained
individuals (46), but these effects are small and unlikely to be
of any clinical significance. Levels of secretory immunoglobu-
103 • AUGUST 2007 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.32.247 on May 12, 2017
and not prolonged (e.g., brisk walking for 1 h/day). Such
exercise is not associated with substantial elevations of circulating IL-6.
Phagocytic neutrophils appear to be activated by an acute
bout of exercise, but show a diminished responsiveness to
stimulation by bacterial lipopolysaccharide (including both
reduced oxidative burst and diminished degranulation responses) after exercise, which can last for many hours (38, 42).
Acute exercise temporarily increases the number of circulating
natural killer (NK) cells, but, following exercise, NK cell
counts drop to less than one-half of normal levels for a couple
of hours; normal resting values are usually restored within 24 h
(46). NK-cell cytolytic activity (per cell) falls after exercise,
and, if the activity is both prolonged and strenuous, the decrease in NK cell counts and cytolytic activity may begin
during the exercise session (46). During recovery from exercise, lymphokine-activated killer cell numbers and activity also
fall below preexercise levels. Acute exercise has been shown to
diminish the proliferative response of lymphocytes to mitogens
(24) and decrease the expression of an early activation marker
(CD69) in response to stimulation with mitogen (43). When the
exercise bout is strenuous and very prolonged (⬎1.5 h), the
number of circulating lymphocytes may be decreased below
preexercise levels for several hours after exercise, and the
T-lymphocyte CD4⫹/CD8⫹ ratio is decreased (2).
Antigen-presenting cell function is also affected by exercise:
exercise-induced reductions in macrophage major histocompatibility complex class II expression and antigen-presenting
capacity have been documented (56). Both T-memory
(CD45RO⫹) and T-naive (CD45RA⫹) cells increase temporarily during exercise, but the CD45RO⫹/CD45RA⫹ ratio
tends to increase due to the relatively greater mobilization of
the CD45RO⫹ subset (11, 22). The functional significance, if
any, of this temporary shift is unclear at present. Following
prolonged, strenuous exercise, the production of immunoglobulins by B lymphocytes is inhibited, and delayed-type
hypersensitivity responses to subdermal antigen injection (a
marker of the cell-mediated immune response) are diminished
(4). These changes during early recovery from exercise would
appear to weaken the potential immune response to pathogens
and have been suggested to provide an “open window” for
infection, representing the most vulnerable time period for an
athlete in terms of their susceptibility to contracting an infection (33).
Invited Review
696
IMMUNE FUNCTION IN SPORT AND EXERCISE
J Appl Physiol • VOL
very small number of studies that have established a relationship between some surrogate measure of immune function and
infection incidence in athletes. A few studies on soldiers during
intensive periods of military training have also reported a
negative relationship between s-IgA concentration and occurrence of URTI (6), although others have not (17, 53). In one
recent study, an increased URTI incidence during 4 wk of
intense military training was significantly correlated with
decreased numbers of circulating NK cells (17). However,
in these situations, the training often involves not only
strenuous physical activity, but also dietary energy deficiency, sleep deprivation, and psychological challenges.
These multiple stressors are likely to induce a pattern of
immunoendocrine responses that amplify the exercise-induced alterations.
THE POSTEXERCISE SORE THROAT: AIRWAY INFECTION
OR INFLAMMATION?
Self-reporting of symptoms of URTI using questionnaires
has been used in a number of studies designed to evaluate the
effects of acute, prolonged exercise (e.g., running a marathon)
or periods of intensified training on infection incidence. However, this approach leaves such studies open to the criticism
that the reporting of symptoms (e.g., sore throat, runny nose,
congestion, fever) is subjective and that factors other than
infection (e.g., allergies, inhalation of air pollutants, airway
inflammation) could also cause some of these symptoms.
Recently, a surveillance study was conducted over a 5-mo
summer/autumn competition season to identify the pathogenic
etiology and symptomatology of upper respiratory illness
(URI) in highly trained elite athletes (n ⫽ 32), recreationally
competitive athletes (n ⫽ 31), and untrained sedentary controls
(n ⫽ 20) (47). Nasopharyngeal and throat swabs were collected
on subjects presenting with two or more defined URI symptoms. Swabs were analyzed using microscopy, culture, and
polymerase chain reaction testing for bacterial, viral, chlamydial, and mycoplasmal respiratory pathogens. The Wisconsin
Upper Respiratory Symptom Survey (WURSS-44) questionnaire was administered to assess the daily symptomatology and
functional impairment. A total of 37 URI episodes in 28
subjects were reported (9 controls, 7 recreationally competitive
exercisers, and 21 elite athletes). The overall distribution mimicked the “J”-shaped curve with rate ratios for illness higher in
both the control (1.93, 95% confidence interval: 0.72–5.18) and
elite (4.50, 95% confidence interval: 1.91–10.59) cohorts than
the referent recreationally competitive athlete cohort. However, of these 37 episodes, infectious agents were identified
in only 11 (30%) (2 control, 3 recreationally competitive
exercisers, and 6 elite athletes). No pathogens were identified in 26 episodes of URI. Specific global symptom, total
symptom, and functional impairment severity scores were
higher in subjects with an infectious URI episode, particularly on illness days 3–5. These findings strongly suggest
that URI in elite athletes are seldom infectious, and the
symptomatology is distinct between infectious and noninfectious episodes. In future research, noninfectious causes
of URI should be considered and investigated to identify
alternative mechanisms and mediators.
103 • AUGUST 2007 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.32.247 on May 12, 2017
lins, such as salivary IgA (s-IgA), vary widely between individuals, and, although some early studies indicated that s-IgA
concentrations are lower in endurance athletes compared with
sedentary individuals (54), the majority of more recent studies
indicate that s-IgA levels are generally not lower in athletes
compared with nonathletes, except when athletes are engaged
in periods of very heavy training (12). Furthermore, moderate
exercise training in healthy young adults does not appear to
have an effect on the initiation of a specific antibody response
to vaccination or delayed-type hypersensitivity responses, as
measured by the swelling that arises 48 h after injecting
antigens into the skin (4). These in vivo measures of immune
function are probably more meaningful than in vitro individual
cell-type functional measures, as they represent the whole
system response to challenge.
Athletes commonly intensify their training for a few days or
weeks at certain stages of the season. This may induce a state
of overreaching in which performance is temporarily reduced,
but, following a period of taper with only light training, results
in supercompensation and an increase in performance. Several
studies in recent years have investigated the effects of short
periods of intensified training on resting immune function and
on immunoendocrine responses to endurance exercise. These
studies indicate that several indexes of leukocyte function,
including neutrophil and monocyte oxidative burst, T-lymphocyte CD4⫹/CD8⫹ ratios, mitogen-stimulated lymphocyte proliferation and antibody synthesis, and NK-cell cytotoxic activity, are sensitive to increases in the training load in already
well-trained athletes (15, 20, 21, 41, 55). Even following
relatively short periods (1–3 wk) of intensified training,
marked reductions in neutrophil function, lymphocyte proliferation, s-IgA, and the circulating number of T cells producing
IFN-␥ have been observed (12, 20, 21). Thus, with chronic
periods of very heavy training, several aspects of both innate
and adaptive immunity are depressed, but athletes are not
clinically immune deficient. In other words, exercise-induced
immune dysfunction does not put athletes in danger of serious
illness, but it could be sufficient to increase the risk of picking
up common infections such as URTI or influenza should the
dreaded outbreak occur.
Several longitudinal studies have monitored immune function in high-level athletes such as cyclists (1), swimmers (12,
15), and footballers (5, 8, 39) over the course of a competitive
season. In a recent study of American football players, the
incidence of URTI was increased during intense training, and
it was reported that the secretion rate of s-IgA (which represents the amount of s-IgA available on the mucosal surfaces for
protection against pathogens) was significantly and inversely
related to URTI incidence (8). In an earlier, much cited study,
the impact of long-term training on systemic and mucosal
immunity was assessed prospectively in a cohort of elite
Australian swimmers over a 7-mo training season in preparation for the national championships (12, 15). The results
indicated significant depression of resting serum and salivary
immunoglobulin concentrations in athletes, associated with
long-term training at an intensive level. Furthermore, resting
s-IgA concentrations at the start of the training period showed
significant inverse correlation with infection rates, and the
number of infections observed in the swimmers was predicted
by the preseason and mean pretraining s-IgA levels. These
studies on mucosal immunity in athletes are representative of a
Invited Review
IMMUNE FUNCTION IN SPORT AND EXERCISE
CAN EXERCISE-INDUCED IMMUNODEPRESSION BE
PREVENTED, AND DO WE WANT TO PREVENT IT?
be an important mechanism leading to an increased risk of
infection after prolonged exercise bouts (32).
Pedersen’s group, however, have argued that the reduction
in the IL-6 response to exercise may be a double-edged sword,
as IL-6 has several metabolic effects and shared mechanisms
exist regarding immune impairment and training adaptation
(48). Attenuating the IL-6 response to exercise will also inhibit
lipolysis (48), reduce the anti-inflammatory effects of exercise,
and attenuate the expression of a number of metabolic genes in
the exercised muscle (37). In other words, it is possible that
antioxidant supplementation and/or carbohydrate ingestion
during exercise sessions could limit adaptation to training.
However, it can also be argued that carbohydrate intake during
training allows the athlete to work harder and longer, and as yet
there is no evidence that physiological and performance adaptations are impaired by carbohydrate intake during training
sessions. Further research is needed to determine how nutrient
intake might affect the transcriptional regulation of metabolic
genes in skeletal muscle and what, if any, consequences this
has for training adaptation or even long-term health benefits.
The concern for athletes is that, although these nutritional
interventions may reduce their risk of infection, another effect
may be to limit their hard-earned adaptation to training.
A SMALL PRICE TO PAY FOR LONG-TERM
HEALTH BENEFITS?
Blood markers of inflammation are strongly associated with
chronic disease in the older population, and inflammation has
been implicated in the pathology of several cardiovascular and
metabolic diseases. Evidence is now emerging that exercise
has anti-inflammatory effects. Individuals who are physically
active on a regular basis have a reduction in the levels of
biomarkers that are used to assess systemic inflammation. For
example, higher levels of habitual physical activity are associated with lower mitogen-stimulated inflammatory cytokine
production, lower skeletal muscle inflammatory protein content, lower adipokine production, and lower serum levels of
Fig. 2. Simplified summary of the results of activating the TLR
signaling pathway. Binding of certain pathogen molecules (e.g.,
LPS) or endogenous danger signal molecules, such as heat shock
proteins (HSPs), to TLRs leads to activation of the antigenpresenting cell and subsequent activation of T cells that it
interacts with. Antigen-presenting cells take up antigen via endocytic pattern recognition receptors (EPRRs) and process (degrade) it to immunogenic peptides, which are displayed to T-cell
receptors (TCRs) in the polymorphic groove of major histocompatibility complex (MHC) class II molecules after their appearance at the cell surface (which is upregulated by TLR activation).
An interaction occurs between the antigen-presenting cell and the
T cell, as indicated (involving cell surface expression of costimulatory molecules such as CD80 and CD86, which are also
upregulated by TLR activation), usually resulting in cellular
activation and differentiation. Cytokines produced by antigenpresenting cells (stimulated by TLR activation) and T cells result
in inflammation and activation of other immune components.
J Appl Physiol • VOL
103 • AUGUST 2007 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.32.247 on May 12, 2017
Studies from Bente Pedersen’s group in Copenhagen indicate that the release of IL-6 from contracting muscle can be
attenuated by long-term antioxidant supplementation. In a
recent single-blind, placebo-controlled study (8), it was reported that 4 wk of oral supplementation, with a combination
of vitamin C (500 mg/day) and vitamin E (400 IU/day),
markedly attenuated the release of IL-6 from active muscle and
the plasma IL-6 and cortisol response to 3 h of dynamic
two-legged, knee-extensor exercise at 50% of maximal power
output compared with placebo. High levels of circulating IL-6
stimulate cortisol release, and this study provides some strong
evidence that the mechanism of action of the antioxidant
supplementation was via a reduction in IL-6 release from the
muscle fibers of the exercising legs. Attenuating the IL-6 and
cortisol response would be expected to limit the exerciseinduced depression of immune function, and this may be the
mechanism that could explain the reported lower incidence of
URTI symptoms in ultramarathon runners supplemented with
vitamin C (alone or in combination with other antioxidants)
compared with placebo (35, 36).
Consumption of carbohydrate during exercise also attenuates increases in plasma IL-6, catecholamines, ACTH, and
cortisol (27, 29). Carbohydrate intake during exercise also
attenuates the trafficking of most leukocyte and lymphocyte
subsets, including the rise in the neutrophil-to-lymphocyte
ratio, prevents the exercise-induced fall in neutrophil function,
and reduces the extent of the diminution of mitogen-stimulated
T-lymphocyte proliferation following prolonged exercise (16).
Recently, it was shown that consuming 30 – 60 g of carbohydrate per hour during 2.5 h of strenuous cycling prevented both
the decrease in the number and percentage of IFN-␥-positive T
lymphocytes and the suppression of IFN-␥ production from
stimulated T lymphocytes observed on the placebo control trial
(22). IFN-␥ production is critical to antiviral defense, and it has
been suggested that the suppression of IFN-␥ production may
697
Invited Review
698
IMMUNE FUNCTION IN SPORT AND EXERCISE
SUMMARY
In summary, acute bouts of exercise cause a temporary
depression of various aspects of immune function (e.g., neutrophil respiratory burst, lymphocyte proliferation, monocyte
TLR, and major histocompatibility complex class II protein
expression) that lasts ⬃3–24 h after exercise, depending on the
intensity and duration of the exercise bout. Postexercise immune function depression is most pronounced when the exercise is continuous, prolonged (⬎1.5 h), of moderate to high
intensity (55–75% maximum O2 uptake), and performed without food intake. Periods of intensified training (overreaching)
lasting 1 wk or more can result in longer lasting immune
dysfunction. Although elite athletes are not clinically immune
deficient, it is possible that the combined effects of small
changes in several immune parameters may compromise resistance to common minor illnesses such as URTI. Protracted
immune depression linked with prolonged training may deterJ Appl Physiol • VOL
mine susceptibility to infection, particularly at times of major
competitions. This is obviously a concern because of the
potential impact of an infectious episode on exercise performance. It is not really a concern for the general population, as
individuals do not need to indulge in heavy training loads to
obtain the health benefits of exercise that may well be proven
to be due, in large part, to its anti-inflammatory effects.
Hundreds of studies have now been conducted that confirm
both acute and chronic effects of exercise on the immune
system, yet there are still very few studies that have been able
to show a direct link between exercise-induced immune depression and increased incidence of confirmed illness in athletes. This is an important issue that needs to be addressed in
future studies, although it must be recognized that this is a
difficult task. Even among the general population, we do not
know the impact of small changes in specific immune parameters on risk of infection. Most clinical studies have only been
concerned with the risk of life-threatening illness in immunodeficient patients, not with the risks of picking up common
infections such as colds and flu.
REFERENCES
1. Baj Z, Kantorski J, Majewska E, Zeman K, Pokoca L, Fornalczyk E,
Tchorzewski H, Sulowska Z, Lewicki R. Immunological status of
competitive cyclists before and after the training season. Int J Sports Med
15: 319 –24, 1994.
2. Berk LS, Ton SA, Nieman DC, Eby EC. The suppressive effect of stress
from acute exhaustive exercise on T-lymphocyte helper/suppressor ratio in
athletes and non-athletes. Med Sci Sports Exerc 18: 706 –710, 1986.
3. Blannin AK, Chatwin LJ, Cave R, Gleeson M. Effects of submaximal
cycling and long-term endurance training on neutrophil phagocytic activity in middle-aged men. Br J Sports Med 30: 125–129, 1996.
4. Bruunsgaard H, Hartkopp A, Mohr T, Konradsen H, Heron I, Mordhorst CH, Pedersen BK. In vivo cell-mediated immunity and vaccination
response following prolonged, intense exercise. Med Sci Sports Exerc 29:
1176 –1181, 1997.
5. Bury T, Marechal R, Mahieu P, Pirnay F. Immunological status of
competitive football players during the training season. Int J Sports Med
19: 364 –368, 1998.
6. Carins J, Booth C. Salivary immunoglobulin-A as a marker of stress
during strenuous physical training. Aviat Space Environ Med 73: 1203–
1207, 2002.
7. Ekblom B, Ekblom O, Malm C. Infectious episodes before and after a
marathon race. Scand J Med Sci Sports 16: 287–293, 2006.
8. Fahlman MM, Engels HJ. Mucosal IgA and URTI in American college
football players: a year longitudinal study. Med Sci Sports Exerc 37:
374 –380, 2005.
9. Fischer CP, Hiscock NJ, Penkowa M, Basu S, Vessby B, Kallner A,
Sjoberg LB, Pedersen BK. Vitamin C and E supplementation inhibits the
release of interleukin-6 from contracting human skeletal muscle. J Physiol
558: 633– 645, 2004.
10. Friman G, Ilback NG. Acute infection: metabolic responses, effects on
performance, interaction with exercise, and myocarditis. Int J Sports Med
19: S172–S182, 1998.
11. Gannon GA, Rhind S, Shek PN, Shephard RJ. Naı̈ve and memory T
cell subsets are differentially mobilized during physical stress. Int J Sports
Med 23: 223–229, 2002.
12. Gleeson M. Mucosal immune responses and risk of respiratory illness in
elite athletes. Exerc Immunol Rev 6: 5– 42, 2000.
13. Gleeson M (Editor). Immune Function in Sport and Exercise. Edinburgh:
Elsevier, 2005.
14. Gleeson M, McFarlin BK, Flynn MG. Exercise and Toll-like receptors.
Exerc Immunol Rev 12: 34 –53, 2006.
15. Gleeson M, McDonald WA, Cripps AW, Pyne DB, Clancy RL,
Fricker PA. The effect on immunity of long-term intensive training in
elite swimmers. Clin Exp Immunol 102: 210 –216, 1995.
16. Gleeson M, Nieman DC, Pedersen BK. Exercise, nutrition and immune
function. J Sports Sci 22: 115–125, 2004.
103 • AUGUST 2007 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.32.247 on May 12, 2017
CRP (14). Thus, although extreme exercise stress may impair
immune function and increase susceptibility to infection, this
may not be entirely detrimental to the host and may, by
reducing immune activation and subsequent inflammation, be
one of the mechanisms through which regular exercise benefits
long-term health (Fig. 1).
An accumulation of chronic, low-grade inflammation is
common in individuals who live a sedentary lifestyle; however,
the mechanism underlying this connection is not fully understood. A new and potentially important finding is that, following a prolonged bout of strenuous exercise, the expression of
Toll-like receptors (TLRs) 1, 2, and 4 on monocytes is decreased for at least several hours (14). TLRs are highly conserved transmembrane proteins that play an important role in
the detection and recognition of microbial pathogens, and they
can also be activated by endogenous danger signals of tissue
damage, such as heat shock proteins. The key product of TLR
signaling in antigen-presenting cells is the production of inflammatory cytokines and proteins, and thus the TLR pathway
plays an important role in mediating whole body inflammation
(Fig. 2). Evidence is now emerging that TLRs may be involved
in the link between a sedentary lifestyle, inflammation, and
disease. Recent studies have shown that both acute aerobic and
chronic resistance exercise bouts result in decreased monocyte
cell-surface expression of TLRs (14, 23, 52). Prolonged exercise also results in a decreased induction of costimulatory
molecules and cytokines following stimulation with known
TLR activators (23). Furthermore, a period of chronic exercise
training decreases both inflammatory cytokine production and
the cell-surface expression of TLR4 on monocytes (52). Although these effects may contribute to postexercise immunodepression and the reported higher susceptibility to infection in
athletes, this may be a small price to pay as, over the long term,
a decrease in TLR expression may represent a beneficial effect,
because it decreases the inflammatory capacity of leukocytes,
thus altering whole body chronic inflammation and possibly
reducing the risk of developing chronic disease. The precise
physiological stimulus mediating an exercise-induced decrease
in cell-surface TLR expression is not known; however, a
number of possible signals have been implicated, including
anti-inflammatory cytokines, stress hormones, and heat shock
proteins (14).
Invited Review
IMMUNE FUNCTION IN SPORT AND EXERCISE
J Appl Physiol • VOL
37. Pilegaard H, Keller C, Steensberg A, Helge JW, Pedersen BK, Saltin
B, Neufer PD. Influence of pre-exercise muscle glycogen content on
exercise-induced transcriptional regulation of metabolic genes. J Physiol
541: 261–271, 2002.
38. Pyne DB. Regulation of neutrophil function during exercise. Sports Med
17: 245–258, 1994.
39. Rebelo AN, Candeias JR, Fraga MM, Duarte JA, Soares JM, Magalhaes C, Torrinha JA. The impact of soccer training on the immune
system. J Sports Med Phys Fitness 38: 258 –261, 1998.
40. Roberts JA. Viral illnesses and sports performance. Sports Med 3:
298 –303, 1986.
41. Robson PJ, Blannin AK, Walsh NP, Bishop NC, Gleeson M. The effect
of an acute period of intense interval training on human neutrophil
function and plasma glutamine in endurance-trained male runners.
J Physiol 515: 84P– 85P, 1999.
42. Robson PJ, Blannin AK, Walsh NP, Castell LM, Gleeson M. Effects of
exercise intensity, duration and recovery on in vitro neutrophil function in
male athletes. Int J Sports Med 20: 128 –135, 1999.
43. Ronsen O, Pedersen BK, Oritsland TR, Bahr R, Kjeldsen-Kragh J.
Leukocyte counts and lymphocyte responsiveness associated with repeated bouts of strenuous endurance exercise. J Appl Physiol 91: 425– 434,
2001.
44. Schnare M, Barton GM, Holt AC, Takeda K, Akira S, Medzhitov R.
Toll-like receptors control activation of adaptive immune responses. Nat
Immun 2: 947–950, 2001.
45. Shephard RJ. Physical Activity, Training and the Immune Response.
Carmel, IN: Cooper, 1997.
46. Shephard RJ, Shek PN. Effects of exercise and training on natural killer
cell counts and cytolytic activity: a meta-analysis. Sports Med 28: 177–
195, 1999.
47. Spence L, Nissen MD, Sloots TP, McCormack JG, Locke AS, Pyne
DB, Fricker PA, Brown WJ. Upper respiratory illness aetiology and
symptomatology in elite and recreationally-competitive athletes. Brain
Behav Immun 19: 469 – 470, 2005.
48. Starkie RL, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK.
Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J 17: 884 – 886, 2003.
49. Starkie RL, Rolland J, Angus DJ, Anderson MJ, Febbraio M. Circulating monocytes are not the source of elevations in plasma IL-6 and
TNF-␣ levels after prolonged running. Am J Physiol Cell Physiol 280:
C769 –C774, 2001.
50. Steensberg A, Fischer CP, Keller C, Moller K, Pedersen BK. IL-6
enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol
Endocrinol Metab 285: E433–E437, 2003.
51. Steensberg A, van Hall G, Osada T, Sacchetti M, Saltin B, Pedersen
BK. Production of interleukin-6 in contracting human skeletal muscles can
account for the exercise-induced increase in plasma interleukin-6.
J Physiol 529: 237–242, 2000.
52. Stewart LK, Flynn MG, Campbell WW, Craig BA, Robinson JP,
McFarlin BK, Timmerman KL, Coen PM, Felker J, Talbert E.
Influence of exercise training and age on CD14⫹ cell-surface expression
of toll-like receptor 2 and 4. Brain Behav Immun 19: 389 –397, 2005.
53. Tiollier E, Gomez-Merino D, Burnat P, Jouanin JC, Bourrilhon C,
Filaire E, Guezennec CY, Chennaoui M. Intense training: mucosal
immunity and incidence of respiratory infections. Eur J Appl Physiol 93:
421– 428, 2005.
54. Tomasi TB, Trudeau FB, Czerwinski D. Immune parameters in athletes
before and after strenuous exercise. J Clin Immunol 2: 173–178, 1982.
55. Verde TJ, Thomas SG, Moore RW, Shek P, Shephard RJ. Immune
responses and increased training of the elite athlete. J Appl Physiol 73:
1494 –1499, 1992.
56. Woods J, Lu Q, Ceddia MA, Lowder T. Special feature for the
Olympics: effects of exercise on the immune system: exercise-induced
modulation of macrophage function. Immunol Cell Biol 78: 545–553,
2000.
103 • AUGUST 2007 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.32.247 on May 12, 2017
17. Gomez-Merino D, Drogou C, Chennaoui M, Tiollier E, Mathieu J,
Guezennec CY. Effects of combined stress during intense training on
cellular immunity, hormones and respiratory infections. Neuroimmunomodulation 12: 164 –172, 2005.
18. Heath GW, Ford ES, Craven TE, Macera CA, Jackson KL, Pate RR.
Exercise and the incidence of upper respiratory tract infections. Med Sci
Sports Exerc 23: 152–157, 1991.
19. Keil D, Luebke RW, Pruett SB. Quantifying the relationship between
multiple immunological parameters and host resistance: probing the limits
of reductionism. J Immunol 167: 4543– 4552, 2001.
20. Lancaster GI, Halson SL, Khan Q, Drysdale P, Jeukendrup AE,
Drayson MT, Gleeson M. Effect of acute exhaustive exercise and a 6-day
period of intensified training on immune function in cyclists (Abstract).
J Physiol 548P: O96, 2003.
21. Lancaster GI, Halson SL, Khan Q, Drysdale P, Jeukendrup AE,
Drayson MT, Gleeson M. The effects of acute exhaustive exercise and
intensified training on type 1/type 2 T cell distribution and cytokine
production. Exerc Immunol Rev 10: 91–106, 2004.
22. Lancaster GI, Khan Q, Drysdale PT, Wallace F, Jeukendrup AE,
Drayson MT, Gleeson M. Effect of prolonged strenuous exercise and
carbohydrate ingestion on type 1 and type 2 T lymphocyte distribution and
intracellular cytokine production in humans. J Appl Physiol 98: 565–571,
2005.
23. Lancaster GI, Halson SL, Khan Q, Drysdale P, Jeukendrup AE,
Drayson MT, Gleeson M. The physiological regulation of toll-like
receptor expression and function in humans. J Physiol 563: 945–955,
2005.
24. Mackinnon LT. Advances in Exercise and Immunology. Champaign, IL:
Human Kinetics, 1999.
25. Matthews CE, Ockene IS, Freedson PS, Rosal MC, Merriam PA,
Hebert JR. Moderate to vigorous physical activity and the risk of
upper-respiratory tract infection. Med Sci Sports Exerc 34: 1242–1248,
2002.
26. Moynihan JA, Callahan TA, Kelley SP, Campbell LM. Adrenal hormone modulation of type 1 and type 2 cytokine production by spleen cells:
dexamethasone and dehydroepiandrosterone suppress interleukin-2, interleukin-4, and interferon-gamma production in vitro. Cell Immunol 184:
58 – 64, 1998.
27. Nehlsen-Cannarella SL, Fagoaga OR, Nieman DC, Henson DA,
Butterworth DE, Schmitt RL, Bailey EM, Warren BJ, Utter A, Davis
JM. Carbohydrate and the cytokine response to 2.5 h of running. J Appl
Physiol 82: 1662–1667, 1997.
28. Nieman DC. Exercise, infection and immunity. Int J Sports Med 15:
S131–S141, 1994.
29. Nieman DC. Influence of carbohydrate on the immune responses to
intensive, prolonged exercise. Exerc Immunol Rev 4: 64 –76, 1998.
30. Nieman DC, Johansen LM, Lee JW, Arabatzis K. Infectious episodes
in runners before and after the Los Angeles Marathon. J Sports Med Phys
Fitness 30: 316 –328, 1990.
31. Niess AM, Dickhuth HH, Northoff H, Fehrenbach E. Free radicals and
oxidative stress in exercise–immunological aspects. Exerc Immunol Rev 5:
22–56, 1999.
32. Northoff H, Berg A, Weinstock C. Similarities and differences of the
immune response to exercise and trauma: the IFN-␥ concept. Can
J Physiol Pharmacol 76: 497–504, 1998.
33. Pedersen BK, Bruunsgaard H. How physical exercise influences the
establishment of infections. Sports Med 19: 393– 400, 1995.
34. Peters EM, Bateman ED. Ultramarathon running and URTI: an epidemiological survey. S Afr Med J 64: 582–584, 1983.
35. Peters EM, Goetzsche JM, Grobbelaar B, Noakes TD. Vitamin C
supplementation reduces the incidence of post-race symptoms of upper
respiratory tract infection in ultramarathon runners. Am J Clin Nutr 57:
170 –174, 1993.
36. Peters EM, Goetzsche JM, Joseph LE, Noakes TD. Vitamin C as
effective as combinations of anti-oxidant nutrients in reducing symptoms
of upper respiratory tract infections in ultramarathon runners. S A J Sports
Med 11: 23–27, 1996.
699