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The anti-inflammatory effects of exercise: Mechanisms and implications for the prevention and treatment of disease

  • Translational Chemical Biology research group -TCBrg


Regular exercise reduces the risk of chronic metabolic and cardiorespiratory diseases, in part because exercise exerts anti-inflammatory effects. However, these effects are also likely to be responsible for the suppressed immunity that makes elite athletes more susceptible to infections. The anti-inflammatory effects of regular exercise may be mediated via both a reduction in visceral fat mass (with a subsequent decreased release of adipokines) and the induction of an anti-inflammatory environment with each bout of exercise. In this Review, we focus on the known mechanisms by which exercise - both acute and chronic - exerts its anti-inflammatory effects, and we discuss the implications of these effects for the prevention and treatment of disease.
The prevalence of obesity continues to rise worldwide
and is being accompanied by a proportional increase in
the incidence of other medical conditions, such as type2
diabetes mellitus (T2D). Such conditions are associated
with derangements in the interplay between metabolic
and immune processes (immunometabolism)1. Moreover,
obesity is associated with cardiovascular disease (CVD),
chronic obstructive pulmonary disease, colon cancer,
breast cancer, dementia and depression. Inflammation
appears to be aetiologically linked to the pathogenesis
of all of these conditions2–6, and the development of a
chronic low-grade inflammatory state has been estab-
lished as a predictor of risk for several of them7. This
inflammatory state is indicated by elevated levels of cir-
culating inflammation markers, such as interleukin-6
(IL-6), tumour necrosis factor (TNF) and C-reactive pro-
tein (CRP). Importantly, physical inactivity and sedentary
behaviour also increase the risk of these conditions5,811.
An inactive lifestyle leads to the accumulation of visceral
fat, and this is accompanied by adipose tissue infiltration
by pro-inflammatory immune cells, increased release of
adipokines and the development of a low-grade systemic
inflammator y state4. This low-grade systemic inflamma-
tion has, in turn, been associated with the development of
insulin resistance, atherosclerosis, neurodegeneration and
tumour growth6–8 (FIG.1). Exercise has anti-inflammatory
effects, and therefore, in the long term, regular physical
activity can protect against the development of chronic
diseases8–11 (TABLE1). In addition, exercise can be used as
a treatment to ameliorate the symptoms of many of these
conditions, and thus the concept that ‘exercise is medi-
cine’12 (BOX1) is increasingly promoted in the hope that
the general population can be persuaded to partake in
more physical activity.
Obviously exercise increases energy expenditure
and burns off some of the body fat that would otherwise
accumulate in individuals who consume more dietary
energy than they need. In this sense, exercise reduces
the risk of developing obesity and excessive adiposity.
Regular exercise also promotes cardiovascular health,
as it improves the blood lipid profile by decreasing the
concentration of plasma triglycerides and low-density
lipoprotein (LDL) particles and increasing the concen-
tration of protective high-density lipoprotein (HDL) cho-
lesterol13. These beneficial alterations in plasma lipids are
presumed to limit the development of atherosclerosis.
However, the protective effect of a physically active life-
style against chronic inflammation-associated diseases
(TABLE1) may additionally be ascribed to an anti-inflam-
matory effect of exercise1416. This may be mediated
not only via a reduction in visceral fat mass (with a
subsequent decreased production and release of pro-
inflammatory adipokines) but also by induction of an
anti-inflammatory environment with each bout of exer-
cise15,16. In this Review, we explain the possible mecha-
nisms by which exercise exerts its anti-inflammatory
Inflammation, Exercise
and Metabolism Research
Group, School of Sport,
Exercise and Health Sciences,
Loughborough University,
Ashby Road, Loughborough,
Leicestershire LE11 3TU, UK.
Correspondence to M.G.
Published online 5 August 2011
Type2 diabetes mellitus
A disorder of glucose
homeostasis that is
characterized by
inappropriately increased
blood glucose levels and
resistance of tissues to the
action of insulin. Recent
studies indicate that
inflammation in adipose tissue,
liver and muscle contributes to
the insulin-resistant state that
is characteristic of type2
diabetes mellitus, and that
the anti-diabetic actions
of peroxisome proliferator-
activated receptor-γ agonists
result, in part, from their
anti-inflammatory effects in
these tissues.
The anti-inflammatory effects of exercise:
mechanisms and implications for the
prevention and treatment of disease
Michael Gleeson, Nicolette C.Bishop, David J.Stensel, Martin R.Lindley,
Sarabjit S.Mastana and Myra A.Nimmo
Abstract | Regular exercise reduces the risk of chronic metabolic and cardiorespiratory
diseases, in part because exercise exerts anti-inflammatory effects. However, these effects
are also likely to be responsible for the suppressed immunity that makes elite athletes more
susceptible to infections. The anti-inflammatory effects of regular exercise may be mediated
via both a reduction in visceral fat mass (with a subsequent decreased release of adipokines)
and the induction of an anti-inflammatory environment with each bout of exercise. In this
Review, we focus on the known mechanisms by which exercise — both acute and chronic —
exerts its anti-inflammatory effects, and we discuss the implications of these effects for the
prevention and treatment of disease.
© 2011 Macmillan Publishers Limited. All rights reserved
Figure 1 | The effect of diet and physical activity on inflammation and disease. A healthy diet and physical activity
maintain the anti-inflammatory phenotype of adipose tissue, which is marked by small adipocyte size and the presence of
anti-inflammatory immune cells, such as M2-type macrophages and CD4+ regulatory T (TReg) cells. A positive energy balance
and physical inactivity lead to an accumulation of visceral fat and adipose tissue infiltration by pro-inflammatory
macrophages and Tcells. The pro-inflammatory M1 macrophage phenotype predominates and inflamed adipose tissue
releases pro-inflammatory adipokines, such as tumour necrosis factor (TNF), which causes a state of persistent low-grade
systemic inflammation. This may promote the development of insulin resistance, tumour growth, neurodegeneration and
atherosclerosis. Atherosclerosis is exacerbated by the deleterious changes in the blood lipid profile that are associated with
a lack of physical activity. LDL, low-density lipoprotein; IL-6, interleukin-6;TLR, Toll-like receptor.
This term has been recently
introduced to describe the
multilevel interactions between
the metabolic and immune
Factors, including cytokines,
that are secreted from adipose
tissue. Some adipokines
promote inflammatory
responses and metabolic
dysfunction, whereas others
have anti-inflammatory
functions and beneficial effects
on metabolic disorders.
Insulin resistance
A condition characterized by
the inability of cells in the
muscle, liver and adipose
tissue to respond appropriately
to endogenous insulin,
resulting in increased blood
glucose levels.
The storage form of fat found in
adipose tissue.
Low-density lipoprotein
(LDL). A protein–lipid complex
in the blood plasma that
facilitates the transport of
triglycerides, cholesterol and
phospholipids. High blood
levels of LDL are associated
with an increased risk of
coronary heart disease.
High-density lipoprotein
(HDL). A protein–lipid complex
in the blood plasma that
facilitates the transport of
triglycerides, cholesterol and
phospholipids. High blood
levels of HDL are associated
with a decreased risk of
coronary heart disease.
effect and briefly discuss the implications for the use of
exercise as a medicine in the prevention and treatment of
chronic disease. We also consider the impact of intensive
training on infection risk for endurance athletes.
Anti-inflammatory effects of exercise
Recent reviews on the anti-inflammatory effects of
exercise1517 have focused on three possible mecha-
nisms: the reduction in visceral fat mass; increased
production and release of anti-inflammatory cytokines
from contracting skeletal muscle (such molecules are
termed myokines15,18); and reduced expression of Toll-
like receptors (TLRs) on monocytes and macrophages17
(with subsequent inhibition of downstream responses,
such as the production of pro-inflammatory cytokines
and the expression of MHC and co-stimulatory mol-
ecules)19. In addition, mouse studies have revealed that
the anti-inflammatory effects of exercise also rely on
other mechanisms, such as the inhibition of monocyte
and macrophage infiltration into adipose tissue20 and the
phenotypic switching of macrophages within adipose
tissue20. Although these types of analysis are difficult to
conduct in humans, analysis of human peripheral blood
following exercise has revealed a reduction in the circu-
lating numbers of pro-inflammatory monocytes21 and an
increase in the circulating numbers of regulatory T cells
(TReg cells)22,23. This suggests that such mechanisms may
also be involved in the anti-inflammatory effects of exer-
cise in humans. However, there are some limitations in
the study of the immunological effects of exercise (both
acute and chronic) in humans; these types of study and
their limitations are summarized in BOX2.
Reduction in visceral fat mass. The accumulation of
body fat — particularly in the abdomen, liver and mus-
cles — is associated with increased all-cause mortality24
and the development of T2D25, CVD26, dementia27 and
several cancers28. The expansion of the adipose tissue
results in increased production of pro-inflammatory
adipokines, such as TNF, leptin, retinol-binding pro-
tein4, lipocalin2, IL-6, IL-18, CC-chemokine ligand2
(CCL2; also known as MCP1), CXC-chemokine ligand5
and angiopoietin-like protein2 (REF.4). Conversely, the
amounts of anti-inflammatory cytokines (for example,
adiponectin and secreted frizzled-related protein5) are
reduced4. This leads to the development of a persistent
state of low-grade systemic inflammation29.
Regular exercise can reduce waist circumference and
cause considerable reductions in abdominal and visceral
fat, even in the absence of any loss of body weight, in
both men and women regardless of age30. Furthermore,
regular exercise results in higher circulating levels of
adiponectin and lower levels of several circulating pro-
inflammatory adipokines, including IL-6, TNF, retinol-
binding protein4 and leptin31–33. It is not known whether
the levels of the other adipokines (mentioned above)
are reduced in the blood following exercise, and further
research is needed to address this. So, increased physical
activity can bring about a reduction in systemic inflam-
mation29 via a decrease in pro-inflammatory adipokine
secretion, which is a direct result of lowering the amount
of fat stored in abdominaldepots.
Release of IL‑6 from contracting muscle. At rest, approx-
imately 30% of circulating IL-6 arises from the adipose
tissue34, but only about 10% of this can be attributed to
the adipocytes35 with the remainder coming mostly from
adipose tissue-resident macrophages. Other sources of
circulating IL-6 include blood leukocytes (predomi-
nantly monocytes), the brain and the liver. During and
following exercise of sufficient load, the active skeletal
muscle markedly increases both cellular and circulat-
ing levels of IL-6 (REF.36). With prolonged exercise
(over 2.5hours), IL-6 levels can increase over 100-fold,
although more modest increases are reported with exer-
cise of a shorter duration37. Increases have also been
© 2011 Macmillan Publishers Limited. All rights reserved
Table 1 | A summary of the associations between physical activity and major diseases*
Disease Evidence that physical activity may lower disease risk and/or have therapeutic value in
treating disease
CHD A large body of epidemiological evidence demonstrates that high levels of physical activity and physical
fitness are associated with a lower risk of developing CHD. RCTs show that regular physical activity can
favourably modify CHD risk factors, including (but not limited to) dyslipidaemia, hypertension and obesity.
RCTs also show that physical activity improves survival in CHD patients.
Stroke Evidence suggests that high levels of physical activity and physical fitness reduce the risk of stroke,
although the data are not as compelling as those for CHD. RCTs show that physical activity can lower (but
not necessarily normalize) blood pressure in hypertensive individuals.
Cancer High levels of physical activity are associated with a lower risk of colon and breast cancer. Physical activity
may lower cancer risk by systemic mechanisms (such as reduced body fat and insulin levels, and enhanced
immune function) and site-specific mechanisms (namely, reduced levels of sex steroid hormones for
breast cancer, and decreased bowel transit time for colon cancer). Some observational and RCT evidence
supports a therapeutic role for physical activity in preserving mobility and function in cancer patients.
T2D Observational epidemiological evidence consistently demonstrates an association between high levels of
physical activity and/or fitness and a reduced risk of developing T2D. RCTs show that lifestyle intervention
(diet and physical activity) can lower body mass, improve glucose tolerance and reduce the risk of
developing T2D in high-risk patients. In patients with T2D, high levels of physical activity and physical
fitness are associated with a reduced risk of CHD and all-cause mortality.
Dementia Observational epidemiological studies indicate that higher levels of physical activity are associated with
a lower risk of cognitive decline and dementia in older adults. Some limited evidence is available from
RCTs to suggest that physical activity induces modest improvements in cognition in individuals who are at
increased risk of Alzheimer’s disease or other forms of dementia.
Other There is some evidence from observational and intervention studies to support a role for physical
activity in enhancing physical function and improving quality of life in those suffering from chronic heart
failure, chronic obstructive pulmonary disease, depression, intermittent claudication, osteoarthritis and
CHD, coronary heart disease; RCT, randomized controlled trial; T2D, type2 diabetes mellitus. *See REFS8,9 for further detail.
Regulatory T cells
(TReg cells). A specialized
subpopulation of Tcells that
acts to suppress activation of
the immune system and
thereby maintains immune
system homeostasis and
tolerance to self antigens.
These cells are involved in
shutting down immune
responses after they have
successfully tackled invading
microorganisms, and also in
regulating immune responses
that may potentially attack
one’s own tissues
A regulatory hormone that is
produced by adipocytes. When
released into the circulation, it
influences the hypothalamus to
control appetite, and its
production correlates with the
amount of adipose tissue.
A cytokine released from
adipocytes that has
anti-inflammatory effects and
acts as an insulin sensitizer.
A steroid hormone secreted
from the adrenal cortex in
response to stress that has
anti-inflammatory as well as
catabolic effects.
A catecholamine secreted from
the adrenal medulla in
response to stress that has
effects on the cardiovascular
system (for example, increased
heart rate and peripheral
vasoconstriction) and on
metabolism (for example,
increased glycogen breakdown
and lipolysis). It also has some
immunosuppressive effects (for
example, decreased
pro-inflammatory cytokine
production by monocytes and
noted using intermittent exercise protocols of relatively
short duration38. The increase in IL-6 during exercise
is transient, normally returning to resting levels within
1hour after exercise. The plasma IL-6 concentration
increases exponentially with exercise duration, and a
major stimulus of its synthesis and release appears to be a
fall in muscle glycogen content39,40. Increases in intracel-
lular calcium levels and increased formation of reactive
oxygen species are also capable of activating transcrip-
tion factors that are known to regulate IL-6 synthesis37.
The transient rise in circulating IL-6 during exer-
cise appears to be responsible for a subsequent rise in
circulating levels of the anti-inflammatory cytokines
IL-10 and IL-1 receptor antagonist (IL-1RA), and it
also stimulates the release of cortisol from the adrenal
glands41. This is demonstrated with the observation
that intravenous infusion of IL-6 mimics the acute
anti-inflammatory effects of a bout of exercise, both
with regard to elevation of plasma IL-10, IL-1RA and
cortisol41 and with regard to suppression of endotoxin-
stimulated increases in TNF levels42.
IL-1RA is secreted mainly by monocytes and mac-
rophages and inhibits the pro-inflammatory actions of
IL-1β43. IL-10 is known to be produced primarily by TReg
cells but also by T helper2 (TH2) cells, TH1 cells, TH17
cells, monocytes, macrophages, dendritic cells (DCs),
Bcells and CD8+ Tcells44. Irrespective of the cellular
source, the principal function of IL-10 appears to be the
downregulation of adaptive immune responses45 and
minimization of inflammation-induced tissue damage.
In detail, IL-10 downregulates the expression of MHC
molecules, intercellular adhesion molecule1 (ICAM1)
and the co-stimulatory molecules CD80 and CD86 on
antigen-presenting cells, and it has also been shown to
promote the differentiation of DCs expressing low lev-
els of MHC classII, CD80 and CD86 (REF.44). In addi-
tion, IL-10 downregulates or completely inhibits the
expression of several pro-inflammatory cytokines and
other soluble mediators, thereby further compromising
the capacity of effector Tcells to sustain inflammatory
responses44,45. Thus, IL-10 is a potent promoter of an
Circulating levels of IL-10 are lower in obese subjects,
and acute treatment with IL-10 prevents lipid-induced
insulin resistance46. Moreover, IL-10 increases insulin
sensitivity and protects skeletal muscle from obesity-
associated macrophage infiltration, increases in inflam-
matory cytokines and the deleterious effects of these
cytokines on insulin signalling and glucose metabolism46.
The action of IL-6 and the subsequent cascade
ofanti-inflammatory cytokines is not the only mecha-
nism responsible for the health benefits that are associ-
ated with exercise, as elevations of IL-6 do not occur
with short durations of low to moderate intensity exer-
cise37 despite the known health benefits (for example,
reduced risk of heart disease) associated with only very
moderate increases in physical activity above that of a
sedentary lifestyle47,48.
Increased levels of circulating cortisol and adrenaline.
Secretion of the adrenal hormones cortisol and adrenaline
is increased during exercise owing to activation of the
hypothalamic–pituitary–adrenal axis and the sympathetic
nervous system (SNS). Impulses from the motor centres
© 2011 Macmillan Publishers Limited. All rights reserved
adrenal axis
A major component of the
stress system that consists of
the paraventricular nucleus
(PVN) of the hypothalamus, the
anterior pituitary gland and the
adrenal cortices. Corticotropin-
releasing hormone and
vasopressin secreted by PVN
neurons into the hypophyseal
portal system stimulate
pituitary cells to produce and
secrete adrenocorticotropic
hormone (ACTH) into the
general circulation. ACTH then
stimulates cortisol secretion by
the adrenal glands.
Sympathetic nervous
A part of the nervous system
that serves to accelerate the
heart rate, constrict blood
vessels, raise blood pressure
and mobilize metabolic fuels. It
is responsible for the
‘fight-or-flight response’ to
stress and physical activity
(that is, the non-volitional
preparation of the organism for
emergency situations).
A peptide hormone secreted
from the anterior pituitary
gland that stimulates the
release of cortisol from the
adrenal glands.
in the brain as well as afferent impulses from work-
ing muscles elicit an intensity-dependent increase in
sympatho adrenal activity. These neural signals also
induce the release of some hypothalamic releasing fac-
tors, which increase the secretion of certain pituitary hor-
mones, including adrenocorticotropic hormone (ACTH)49.
Increased SNS activity stimulates the release of the
catecholamines adrenaline and noradrenaline from the
adrenal medulla within seconds of the onset of exercise,
and ACTH stimulates cortisol secretion from the adre-
nal cortex within minutes. These hormonal responses
usually precede the rise in circulating concentrations of
cytokines, and the magnitude of the elevations in plasma
cortisol and adrenaline levels is related to the intensity
and duration of exercise49. Cortisol is known to have
potent anti-inflammatory effects50, and catecholamines
downregulate the lipopolysaccharide (LPS)-induced
production of cytokines (including TNF and IL-1β) by
immune cells51. Cortisol secretion is also augmented by
the aforementioned rise in circulating IL-6 from work-
ing skeletal muscle41. Thus, hormones, myokines and
cytokines all contribute to the anti-inflammatory effect
of exercise (FIG.2).
Inhibition of macrophage infiltration into adipose
tissue. Macrophages and Tcells that infiltrate adipose
tissue in obesity are known to regulate the adipose tis-
sue’s inflammatory state52,53. Thus, the migration of
peripheral blood mononuclear cells (PBMCs) towards
sites of inflammation, including adipose tissue and dam-
aged vascular endothelium, is central to the development
of sustained tissue inflammation54–57. It has been sug-
gested that the increased size of the adipocytes, rather
than an overall increase in adipose tissue mass, triggers
macrophage infiltration58, and it has been speculated that
the recruitment of macrophages may be stimulated by the
chemokines CCL2 and CCL3 (also known as MIP1α)55,59.
Exercise may limit the movement of PBMCs into
inflamed adipose tissue, although there is little evidence
to support this at present20. The migration of PBMCs
from the circulation into the tissues is a tightly regu-
lated process. It requires a gradient of chemokines that
are released from the inflamed tissue (including from
immune cells residing within the tissue), the expression
of complimentary chemokine receptors on PBMCs and
the expression of adhesion molecules on both immune
and endothelial cells. Acute bouts of exercise reduce
Tcell migration towards the supernatants from human
airway epithelial BEAS-2B cells infected with rhinovirus
in a manner that is independent of any involvement of
adhesion molecules or exercise-induced elevations of cor-
tisol or catecholamines60. However, it is known that the
stress induced by acute exercise results in the release of
chemokines from multiple sources into the circulation61,
and sustained exposure of PBMCs to physiological con-
centrations of chemokines (including CCL2) results in
chemokine receptor internalization62. This is thought to
serve as a negative feedback mechanism to reduce migra-
tion and thereby terminate the accumulation of PBMCs
in inflamed tissue. It is possible, therefore, that an active
lifestyle causes repeated short-lasting elevations in plasma
levels of chemokines, which act over time to downregu-
late expression of their receptors on PBMCs and restrict
migration of these cells towards adipose tissue. However,
this potential mechanism needs to be explored further
inhumans. Conversely, there is some evidence from
murine studies in support of the concept that exercise
inhibits the release of chemokines from adipose tissue
and in this way reduces macrophage infiltration, although
whether this occurs in humans is not clear54,63.
In a mouse model, training was reported to decrease
the tissue expression of ICAM1 (REF.20), which has a
role in the adhesion of inflammatory cells to vascular
endothelium, the extracellular matrix and epithelium,
and also mediates interactions between Tcells and target
cells. Signal transduction downstream of these interac-
tions leads to Tcell activation, proliferation, cytotoxicity
and cytokine production. ICAM1 expression is known
to be increased in obesity in humans64, and blocking
ICAM1 in obese mice prevented macrophage infiltration
into adipose tissue65. Moreover, circulating ICAM1 levels
were reduced in patients with T2D following 6months
of progressive aerobic exercise training, without changes
in body mass or waist circumference66. Obviously, fur-
ther studies in humans are required to ascertain the
effect of exercise training on ICAM1 expression in adi-
pose tissue, but ICAM1 might also have a role in the
exercise-induced reduction of macrophage infiltration
into adiposetissue.
Macrophage activation results in two separate polari-
zation states: M1 and M2 (REF.67). M1-type macrophages
produceTNF, IL-6 and nitric oxide, whereas M2-type
macrophages produce anti-inflammatory cytokines and
arginase. Therefore, M1-type macrophages induce an
inflammatory state and M2-type macrophages subdue
Box 1 | Exercise is medicine
Exercise is now considered to be not only of prophylactic value, but also an effective
therapy for many conditions and diseases. Perhaps the strongest evidence for the role
of exercise in disease prevention comes from randomized controlled trials that
evaluated the effectiveness of lifestyle intervention in preventing type2 diabetes
mellitus (T2D)103. These studies have demonstrated conclusively that lifestyle
intervention (combined diet and exercise) is effective in preventing T2D in groups of
individuals who are at high risk of the disease. A limitation of these studies is that the
independent effects of exercise and diet in preventing T2D were not isolated. However,
the effectiveness of exercise alone is supported by the findings of the Finnish Diabetes
Prevention Study104. Among those in the intervention group of this study who did not
reach the goal of losing 5% of their initial body mass, but who achieved the goal of
exercising for more than 4hours per week, the odds ratio of developing T2D was 80%
lower than in intervention participants who remained sedentary.
In addition, exercise appears to have major benefits for the treatment of T2D105, and
prospective observational studies indicate that high levels of physical activity and/or
physical fitness are effective in reducing the risk of cardiovascular disease (CVD) and
all-cause mortality in T2D patients106,107. Inflammation has been implicated in the
pathogenesis of T2D108, and it is therefore likely that the therapeutic benefits of
exercise for those with T2D are due, at least in part, to the well-established
anti-inflammatory effects of regular exercise14–16.
There is also good evidence that exercise is effective in preventing several other
major diseases, particularly CVD109, breast cancer102,110 and colon cancer102,111, and some
evidence supports a role for exercise in preventing dementia112. Other studies have
suggested that exercise could be used as a therapy for chronic obstructive pulmonary
disease, chronic kidney disease, asthma and osteoporosis8,9.
© 2011 Macmillan Publishers Limited. All rights reserved
A catecholamine secreted from
sympathetic nerve endings
that has effects on the
cardiovascular system (for
example, increased heart rate
and peripheral
vasoconstriction) and on
metabolism (for example,
increased glycogen breakdown
and lipolysis). It also has some
immunosuppressive effects (for
example, decreased
pro-inflammatory cytokine
production by monocytes and
M1-type macrophages
Macrophages that are
activated in the presence of
TH1-type cytokines, such as
interferon-γ, and produce,
among other molecules,
inducible nitric oxide synthase
and nitric oxide.
M2-type macrophages
Macrophages that are
activated in the presence of
TH2-type cytokines, such as
interleukin-4 (IL-4) or IL-13,
and express arginase1, the
mannose receptor CD206 and
the IL-4 receptor α-chain.
inflammation in adipose tissue. Inflamed adipose tis-
sue appears to be associated with a preferential recruit-
ment of M1-type macrophages and/or a phenotypic
switch of adipose tissue macrophages towards the M1
phenotype68. Therefore, it is possible that the attenuated
inflammatory state of adipose tissue that is associated
with chronic exercise training occurs by both suppres-
sion of macrophage infiltration and acceleration of phe-
notypic switching from M1- to M2-type macrophages.
Indeed, a recent study in mice fed a high-fat diet to
induce obesity provided some evidence that exercise
training induces this phenotypic switching from M1-
to M2-type macrophages in adipose tissue and inhibits
M1-type macrophage infiltration into adipose tissue20.
However, studies in humans are still scarce.
Downregulation of TLR expression. TLRs are highly
conserved transmembrane proteins that have an impor-
tant role in the detection of microbial pathogens and in
the recognition of endogenous danger signals released
following tissue damage, such as heat shock proteins69.
Activation of TLR signalling results in increased expres-
sion and secretion of pro-inflammatory cytokines and
thus has an important role in mediating systemic inflam-
mation70. Evidence is now emerging that TLRs may be
involved in the link between a sedentary lifestyle and
inflammation and disease. Exercise training studies
and cross-sectional comparisons between physically
active and inactive subjects have shown that blood
monocytes from physically active individuals have a
reduced inflammatory response to endotoxin stimu-
lation in vit ro. These cells also have decreased TLR4
expression (at both cell surface protein and mRNA lev-
els)17,19, which is associated with decreased inflammatory
cytokine production71.
Following an acute, prolonged bout of strenuous
exercise, the expression of TLR1, TLR2 and TLR4 on
monocytes is decreased for at least several hours19,72,73.
Prolonged exercise also results in a decreased induction
of co-stimulatory molecules and cytokines following
stimulation with known TLR ligands, such as LPS and
zymosan71. Whether this reduction in cell surface expres-
sion of TLRs is due to downregulation of TLR gene
expression, shedding of TLRs from the cell surface or
re-internalization by the cell remains to be established.
The precise physiological stimulus that mediates an
exercise-induced decrease in cell surface TLR expres-
sion is not known; however, several possible signals have
been implicated, including anti-inflammatory cytokines,
stress hormones and heat shock proteins19.
The evidence discussed above points to a downregu-
lation of TLR expression and subsequent downstream
inflammatory signalling cascades with acute exercise.
However, as prolonged exercise increases lipolysis and
elevates plasma levels of free fatty acids, which are
ligands for TLR2 and TLR4 (REF.74), it might be sur-
mised that exercise could induce inflammatory cascades
via activation of TLRs. However, there is no direct evi-
dence for this, and LPS-stimulated cytokine production
by blood monocytes is clearly reduced, not increased,
following prolonged exercise42,71,75.
Reduced numbers of pro‑inflammatory monocytes
in blood. There are two main populations of mono-
cytes: classical (CD14hiCD16) and non-classical
(CD14lowCD16+ or CD14hiCD16+). These subsets differ-
entially express cell surface TLR4, with the inflammatory
CD14lowCD16+ monocytes expressing 2.5 times as much
cell surface TLR4 as the other populations76. Despite
constituting only 10% of the total monocyte popula-
tion, inflammatory monocytes contribute significantly
to the inflammatory potential of the monocyte pool
as a whole77. The percentage of circulating inflamma-
tory monocytes is elevated in patients with rheumatoid
arthritis78, CVD79 and T2D80, and it has been suggested
that inflammatory monocytes play a significant role in
the pathogenesis of several diseases linked to inflamma-
tion. Transient increases in the numbers of inflamma-
tory monocytes have been observed after a single, acute
bout of intense exercise81, followed by a rapid return to
Box 2 | Studying immune responses to exercise in humans
The study of the immunological effects of exercise in humans is a growing area of research, and more than 1,400 original
studies and 500 review articles have been published in the past 15years. Studies either investigate the effects of exercise
as a behavioural or lifestyle factor perse, or use exercise as a non-clinical human model of the body’s response to
physiological stresses, such as sepsis or trauma. There are two main types of exercise used in these investigations in
humans: moderate (recreational) exercise or intensive periods of exercise of differing durations, which may be
continuous or intermittent. Study designs include acute exercise (single bout) protocols, cross-sectional comparisons of
different activity levels and longitudinal studies over a period of weeks or months.
The effects of exercise on immune measures have been assessed in numerous ways, primarily in purified cell
populations or in whole blood. The parameters that are commonly investigated include: phenotypic alterations in
circulating cells; expression of markers of activation or apoptosis; lymphocyte proliferation; cytokine and
immunoglobulin production; natural killer cell cytotoxicity; neutrophil phagocytosis, degranulation and oxidative burst;
and cell chemotaxis or migration. Assays to determine concentrations of soluble markers — such as immunoglobulins,
cytokines, shed adhesion molecules and cytotoxic enzymes — are routinely used in this field. Levels of mucosal immune
factors, particularly salivary IgA, have received much attention in the exercise immunology literature owing to their
established negative association with subsequent respiratory infections in athletic populations96,99,113.
The limitations of many studies in this field are that only peripheral blood measurements have been used in the majority
of investigations into immunological responses to exercise in humans, and that invitro measures have been used
extensively to model the complex situation invivo. However, delayed-type hypersensitivity responses and antibody titres
following vaccination have been used in this regard to good effect in some human exercise studies.
© 2011 Macmillan Publishers Limited. All rights reserved
+. 60(
Figure 2 | Potential mechanisms contributing to the anti-inflammatory effects of
exercise. Activation of the hypothalamic–pituitary–adrenal axis and the sympathetic
nervous system (SNS) leads to the release of cortisol and adrenaline from the adrenal
cortex and medulla, respectively.These hormones inhibit the release of tumour necrosis
factor (TNF) by monocytes.Interleukin-6 (IL-6) produced by contracting skeletal muscle
also downregulates the production of TNF by monocytes and may stimulate further
cortisol release.Acute elevations in IL-6 stimulate the release of IL-1 receptor antagonist
(IL-1RA) from monocytes and macrophages, thus increasing the circulating
concentrations of this anti-inflammatory cytokine.Exercise training mobilizes regulatory
T (TReg) cells (which are a major source of the anti-inflammatory cytokine IL-10) and
decreases the ratio of inflammatory (CD14lowCD16+) monocytes to classical (CD14hiCD16)
monocytes.Following exercise, CD14hiCD16 monocytes express less Toll-like receptor4
(TLR4), and thereby induce a reduced inflammatory response marked by lower levels of
pro-inflammatory cytokines and reduced adipose tissue infiltration. Exercise also
increases plasma concentrations of key inflammatory immune cell chemokines; repeated
elevations of such chemokines may lead to a downregulation of their cellular receptors,
resulting in reduced tissue infiltration.A reduction in adipose tissue mass and adipocyte
size, along with reduced macrophage infiltration and a switch from an M1 to an M2
macrophage phenotype, may contribute to a reduction in the release of pro-inflammatory
cytokines (such as IL-6 and TNF) and an increase in the release of anti-inflammatory
cytokines (such as adiponectin and IL-10) from adipose tissue.
baseline numbers during recovery. However, regular
exercise appears to reduce the proportion of inflamma-
tory monocytes in the circulation in the resting state.
For example, a cross-sectional comparison of healthy,
physically inactive elderly men and women with an age-
matched physically active group indicated that sedentary
people have a twofold higher percentage of circulating
inflammatory monocytes21. Furthermore, 12weeks
of regular exercise training markedly reduced the
percentage of inflammatory monocytes in the inactive
group to the level of the active group, and endotoxin-
stimulated TNF production was reduced substantially
after the training intervention. Based on previous
reports that glucocorticoid therapy selectively depletes
CD14lowCD16+ monocytes82, it is interesting to speculate
that exercise-induced transient spikes in plasma corti-
sol levels may have a role in reducing the number of
CD14lowCD16+ monocytes.
Of course, a reduction in the number of inflamma-
tory monocytes in the blood could also be indicative
of increased monocyte infiltration into the tissues or
migration of pro-inflammatory monocytes into the lym-
phoid organs83. However, this notion is not supported
by murine studies that demonstrate reduced leukocyte
infiltration and inflammation in dermal wound sites
after exercise84. Further analysis and functional studies
are needed in humans to confirm that exercise reduces
the numbers of pro-inflammatory monocytes and that
this contributes to its anti-inflammatoryeffects.
Increased circulating numbers of regulatory Tcells.
CD4+CD25+ TReg cells specifically express the transcrip-
tion factor forkhead boxP3 (FOXP3)85 and suppress
immune responses. Studies show that the depletion of
these cells can lead to autoimmunity and enhances the
immune response to foreign antigens86–89. Interestingly,
one study showed that a 12-week programme of Tai Chi
Chuan exercise induced a substantial increase in circulat-
ing TReg cell numbers22. The production of the TReg cell-
derived cytokines transforming growth factor-β (TGFβ)
and IL-10 in response to invit ro antigenic stimulation was
also markedly increased in PBMCs isolated after this exer-
cise programme. Furthermore, a study of patients with
T2D showed that regular Tai Chi Chuan exercise altered
the balance between TH1, TH2 and TReg cell subsets by
increasing FOXP3 but not TGFβ expression90.
In a study that used a running mouse model, the
responses of circulating TReg cells to moderate- or
high-intensity exercise training were examined. Only
the high-intensity training resulted in increases in TReg
cell numbers, and it was also associated with reduced
pro-inflammatory and increased anti-inflammatory
cytokine expression23. Intriguingly, these findings imply
that high-intensity exercise training might be more ben-
eficial than moderate-intensity training in reducing the
risk of chronic cardiovascular and metabolic diseases,
as a result of its anti-inflammatory effects. This notion
is supported by another recent study that showed that
a combination of high-intensity aerobic plus resistance
exercise training, in addition to daily physical activity,
is required to achieve a significant anti-inflammatory
effect in T2D patients91.
Other factors. During acute exercise, there is a marked
increase in the circulating levels of growth hormone,
prolactin, heat shock proteins and other factors that
have immunomodulatory effects by influencing leuko-
cyte trafficking and functions92. Thus, these molecules
may also contribute to the anti-inflammatory effects of
© 2011 Macmillan Publishers Limited. All rights reserved
Taken together, these findings suggest that each bout
of exercise induces an anti-inflammatory environment.
Various mechanisms can contribute to this (FIG.2), and
it seems likely that their relative importance will vary
depending on the frequency, intensity and duration of
the exercise performed. For low-intensity exercise, such
as brisk walking, it is likely that the control of body fat is
the most important mechanism, but for short periods of
high-intensity exercise and prolonged moderate-intensity
exercise the other anti-inflammatory effects may have an
increasingly importantrole.
The elite athlete paradox
Although regular moderate-intensity exercise is associ-
ated with a reduced incidence of upper respiratory tract
infection compared with a completely sedentary state93,94,
the long hours of hard training that elite athletes under-
take appears to make them more susceptible to upper
respiratory tract infections11,95–98. This is probably
attributable to the anti-inflammatory effects of exercise
inducing a degree of immunosuppression11,98, although
other factors — such as psychological stress, disturbed
sleep and negative energy balance — may contribute to
immunosuppression in elite athletes98. An increased risk
of minor infections may be the (small) price to be paid
for the long-term health benefits of regular exercise at
A recent murine study indicated that intensive exer-
cise training results in an increased anti-inflammatory
cytokine (IL-10) response to antigen exposure23. Mo reo ver,
a study on human endurance athletes revealed that whole
blood cultures from athletes who were prone to illness
during a 4-month period of winter training produced
four times as much IL-10 following antigen stimulation
as blood cultures from athletes who remained illness-free
during the same period99. There is now extensive evidence
from both murine and human studies that IL-10 produc-
tion usually imposes some limits on the effectiveness of
pathogen-specific immune responses, especially innate
immunity and adaptive TH1 cell responses100,101. These
studies suggest that very high training loads induce an
anti-inflammatory state that is sufficient to increase the
risk of minor infections.
Conclusions and remaining questions
Regular exercise reduces the risk of chronic metabolic and
cardiorespiratory diseases (TABLE1), in part because exer-
cise exerts anti-inflammatory effects. The anti-inflam-
matory effects of regular exercise may be mediated via
both a reduction in visceral fat mass (with a subsequent
decreased release of adipokines) and the induction of an
anti-inflammatory environment with each bout of exer-
cise. Various mechanisms may contribute to the genera-
tion of this anti-inflammatory environment, including:
increased release of cortisol and adrenaline from the
adrenal glands; increased production and release of
IL-6 and other myokines from working skeletal muscle;
reduced expression of TLRs on monocytes and macro-
phages (with subsequent inhibition of downstream
pro-inflammatory cytokine production); inhibition
of adipose tissue infiltration by monocytes and mac-
rophages; phenotypic switching of macrophages within
adipose tissue; a reduction in the circulating numbers of
pro-inflammatory monocytes; and an increase in the cir-
culating numbers of TReg cells. These anti-inflammatory
effects of exercise are also likely to be responsible for
the partial immunosuppression that makes elite athletes
more susceptible to common infections.
At present, we do not know the relative importance of
these different anti-inflammatory mechanisms, although
it seems likely that this will depend on the mode, fre-
quency, intensity and duration of the exercise performed.
Intuitively, we might expect IL-6 to assume greater rela-
tive importance when the exercise is prolonged and
glycogen-depleting, whereas catecholamine-mediated
effects are likely to assume greater importance with
shorter duration, high-intensity exercise. High training
loads may be needed to increase circulating numbers of
TReg cells and maximize the anti-inflammatory effects, but
possibly at the cost of a small increase in infection risk.
Further research should establish the mode, intensity
and duration of exercise required to optimize the anti-
inflammatory effects, and it still remains to be estab-
lished whether exercise is always useful as a therapy for
the treatment of patients with inflammation-associated
disorders. Furthermore, we still need to determine the
independent contribution of an exercise-induced reduc-
tion in visceral fat (versus other exercise-induced anti-
inflammatory mechanisms) in reducing inflammation
in adipose tissue, insulin resistance and risk of chronic
disease. Although there is a consensus that exercise train-
ing protects against some types of cancer11,102, it is not
yet known whether this is due to alterations in immuno-
logical and inflammatory mechanisms. Finally, it should
be noted that further research is needed to clearly dem-
onstrate the direct and indirect molecular mechanisms
by which physical exercise influences immune function.
There can be no doubt that regular exercise is beneficial
for health, but a major challenge is to encourage more of
the general population to engage in more ofit.
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Competing interests statement
The authors declare no competing financial interests.
Michael Gleeson’s homepage:
© 2011 Macmillan Publishers Limited. All rights reserved
... Vriens et al. showed positive associations of sedentary behavior (represented by screen time) with body mass index, salivary miRNA-222 and miRNA-146a expression (33), while on the contrary, circulating plasma levels of miRNA-146a were up-regulated after acute physical activity in young endurance athletes (51). It is known that acute physical activity is associated with a transitory immunological/stress response, which in the long-term could be beneficial to the organism (52)(53)(54). In this context, miRNA-146a plays an essential role in the inflammatory signaling in different type of cells and might reflect the inflammatory state after prolonged aerobic physical activity (51). ...
... Wu et al. reported that substituting 30-min of vigorous physical activity for 30-min of sedentary behavior daily was associated with higher methylation levels at HSD11B2 promoter in boys (39). HSD11B genes catalyze the interconversion of cortisol and corticosterone (45), and thereby vigorous acute physical activity might be associated with an increased transitory stress/immunological response (52)(53)(54). Thus, HSD11B could be involved in stress/immunological response to acute physical activity or related to vigorous physical activity levels. ...
... ADRB2 is the main target of catecholamines such as noradrenaline (56) involved in the stress response (e.g., acute physical activity). A single bout of physical activity can increase the secretion of catecholamines, which in turn might decrease the production of pro-inflammatory markers such as IL-1β by immune cells (52). Thus, ADRB2 gene up-regulation in the whole blood after a single bout of intense physical activity could be related to the anti-inflammatory effects of physical activity. ...
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Background The links of sedentary behavior and physical activity with health outcomes in children and adolescents is well known. However, the molecular mechanisms involved are poorly understood. We aimed to synthesize the current knowledge of the association of sedentary behavior and physical activity (acute and chronic effects) with gene expression and epigenetic modifications in children and adolescents.Methods PubMed, Web of Science, and Scopus databases were systematically searched until April 2022. A total of 15 articles were eligible for this review. The risk of bias assessment was performed using the Joanna Briggs Institute Critical Appraisal Tool for Systematic Reviews and/or a modified version of the Downs and Black checklist.ResultsThirteen studies used candidate gene approach, while only 2 studies performed high-throughput analyses. The candidate genes significantly linked to sedentary behavior or physical activity were: FOXP3, HSD11B2, IL-10, TNF-α, ADRB2, VEGF, HSP70, SOX, and GPX. Non-coding Ribonucleic acids (RNAs) regulated by sedentary behavior or physical activity were: miRNA-222, miRNA-146a, miRNA-16, miRNA-126, miR-320a, and long non-coding RNA MALAT1. These molecules are involved in inflammation, immune function, angiogenic process, and cardiovascular disease. Transcriptomics analyses detected thousands of genes that were altered following an acute bout of physical activity and are linked to gene pathways related to immune function, apoptosis, and metabolic diseases.Conclusion The evidence found to date is rather limited. Multidisciplinary studies are essential to characterize the molecular mechanisms in response to sedentary behavior and physical activity in the pediatric population. Larger cohorts and randomized controlled trials, in combination with multi-omics analyses, may provide the necessary data to bring the field forward.Systematic Review Registration[], identifier [CRD42021235431].
... They found aerobic exercise as well as combined aerobic and resistance training are better forms of exercise for improving anthropometric outcomes (15,16). More importantly, regular exercise training plays an essential role in reducing the risk of chronic metabolic and cardiorespiratory diseases partly due to the anti-inflammatory effects of exercise (17). Many meta-analyses and systematic reviews have studied the effect of exercise training on inflammatory cytokines, focusing on people with type 2 diabetes mellitus, metabolic syndrome, middle-aged and older adults, cancer survivors, and others (18)(19)(20)(21). ...
... Therefore, it is of great significance to study the effect of exercise on inflammatory factors in overweight and obese individuals. Previous reviews have discussed the effect of exercise training on chronic inflammation and its underlying mechanisms, arguing that exercise training can reduce chronic systemic inflammation in obese individuals through a variety of mechanisms (17,22). However, the anti-inflammatory effect of exercise training is inseparable from the exercise type and intensity. ...
... IL-6, TNF-a, and CRP are important pro-inflammatory factors, and their levels are elevated in people with obesity (7,17). Studies have shown that exercise training can reduce obesity-related chronic inflammation by affecting the inflammatory mediators from various sources, including adipose tissue, muscle tissue, endothelial cells, and circulating immune cells (22). ...
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Objective This study aimed to compare and rank the effectiveness of aerobic exercise (AE), resistance training (RT), combined aerobic and resistance training (CT), and high-intensity interval training (HIIT) on body composition and inflammatory cytokine levels in overweight and obese individuals by using network meta-analysis (NMA).Methods We searched the PubMed, Cochrane, Embase, Web of Science, and EBSCO databases to identify randomized controlled trials investigating the effects of exercise training on inflammatory cytokines in overweight and obese patients. The retrieval period was from inception to November 2021. Two reviewers independently screened the retrieved articles, extracted the pertinent data, and assessed the risk of bias of the included studies; then, they used Stata 16.0 and Review Manager 5.3 to perform an NMA.ResultsA total of 38 studies involving 1317 patients were included in this study. The results of the NMA indicated that AE had the greatest effect on weight loss (SUCRA=78.3; SMD=−0.51, 95% CI: −0.70, −0.33); CT had the greatest effect on reducing body mass index (SUCRA=70.7; SMD=−0.46, 95% CI: −0.81, −0.10), waist circumference (SUCRA=93.4; SMD=−1.86, 95% CI: −2.80, −0.93), percentage body fat (SUCRA=79.6; SMD=−1.38, 95% CI: −2.29, −0.48), interleukin-6 level (SUCRA=86.4; SMD=−1.98, 95% CI: −3.87, −0.09), and tumor necrosis factor-α level (SUCRA=79.4; SMD=−2.08, 95% CI: −3.75, −0.42); AE (SMD=0.51, 95% CI: −1.68, 2.69), RT (SMD=0.15, 95% CI: −3.01, 3.32), CT (SMD=1.78, 95% CI: −1.35, 4.92), and HIIT (SMD=2.29, 95% CI: −1.27, 5.86) did not significantly increase the adiponectin level.Conclusion The current results suggest that CT is the best exercise modality for improving body composition and inflammatory status in overweight and obese individuals. More rigorous randomized control trials are needed for further validation.Systematic Review Registration, identifier CRD42022303165.
... These cytokines, which are produced and released by many cell types during and after physical exertion, mediate the beneficial effects of exercise on health. Cytokines can also influence metabolism and modify the production of cytokines in other tissues and organs, thus playing a fundamental role in regulating homeostasis and modulating the body's defense against chronic diseases (Gleeson et al., 2011;Benatti and Pedersen, 2015;Febbraio 2017). Many studies have shown increased levels of plasma concentrations of cytokines, such as interleukin-(IL)6, interleukin-(IL)10, tumor necrosis factor (TNF)α, and irisin after vigorous exercise (Peake et al., 2015;Blizzard LeBlanc et al., 2017). ...
... Interestingly, our findings are in accordance with those provided by Gleeson et al. (2011). In the latter study, eighty physically active individuals (46 men, 34 women) trained on average 10 h/week at moderate-to-vigorous intensities; after that, differential leukocyte counts and lymphocyte subsets were determined. ...
... While the total blood leukocyte, neutrophil, monocyte, and lymphocyte counts did not differ between sexes, men had more B and NK cells. Consistent with the present results, the authors concluded that most aspects of immunity were similar between the sexes in an athletic population, with some differences in a few immune variables (Gleeson et al., 2011). ...
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Introduction: Physical exercise can acutely and chronically modulate immunological responses. Women and men have different innate and adaptive immune responses, and in this sense, these two groups may also have different acute immunological responses induced by exercise. In addition, it is essential to understand further whether the effects of physical exercise on the immune system responses depend on sex because limited scientific evidence on this topic is available. This information may allow athletes and coaches to improve the training process, mainly to understand if the physiological impact of given training stimuli in women is similar to that in men. Objective: The present study aimed to investigate the acute effects of continuous submaximal exercise until fatigue on physiological and immunological parameters in amateur female and male runners. Methods: This study included 18 female and 15 male volunteers. Each participant visited the laboratory on four consecutive days. The first visit consisted of medical history taking and explaining the study design. On the second visit, the participants were subjected to an incremental test to determine their maximal rate of oxygen consumption (VO 2max) that was required to prescribe the intensity of the submaximal exercise protocol. On the third visit, the fatiguing exercise protocol was performed at 77%-80% of the VO 2max. During this submaximal exercise, the heart rate, rating of perceived exertion (RPE), and blood lactate were recorded. Blood samples were collected before, immediately after, and 1 h after the fatiguing protocol to analyze the plasma levels of cytokines and creatine kinase (CK) and to count leukocytes. Finally, on the fourth visit, the participants underwent physical evaluations to measure their body composition using dual-energy X-ray absorptiometry (DXA) imaging. Results: The average ages of the female and male groups were 34.2 ± 3.7 and 30.5 ± 4.3 years old, respectively. The female group ran 57 ± 27 min, while the male group ran 52 ± 15 min before fatiguing. In the female group, when comparing before and after the submaximal exercise, marked increases were observed in the following variables: heart rate (from 68.5 to 180.4 bpm), RPE (from 3.6 to 8.2), lactate (from 2.1 to 4.49 mmol/L), and CK (from 89.5 to 126.3 U/L). In addition, the female group showed an increased number of total leukocytes (from 7222.3 to 11162.9 × 10 6 /μl), neutrophils (from 4,403 to 6,480 × 10 6 /μl), and lymphocytes (from 2,342 ± to 3,562 × 10 6 /μl) from pre-to post-submaximal exercise. In the male group, similar elevations in psychophysiological variables were observed, as evidenced by comparing the heart rate (from 52.8 to 184.1 bpm), RPE (from 0.0 to 8.9), lactate (from 2.7 to 7.2 mmol/L), and CK (from 106.2 to 165 U/L) before and after the submaximal exercise. The male group also showed an augmented number of total leukocytes (from 6,245 to 8,050 × 10 6 /μl), neutrophils (from 3,335 to 4,128 × 10 6 /), and lymphocytes (from 2,191 to 3,212 × 10 6 /μl) when comparing pre-and post-submaximal exercise. There were no differences in the changes between women and men for these parameters. Conclusion: The aerobically fatiguing exercise protocol induced pronounced changes in the heart rate, plasma levels of lactate and CK, total leukocyte count, especially the number of neutrophils and lymphocytes, in both sexes. The fatiguing exercise protocol also changed the plasma levels of IL-6 and IL-10 in the female and male groups. Under the present conditions, the physiological changes induced by fatiguing submaximal exercise, including the immunological changes, were not influenced by sex. This study shows that the same aerobic physical exercise can alter immunological parameters in women and men, and this response is similar between sexes.
... Although regular exercise benefits physical and mental health (Flynn and McFarlin, 2006;Gleeson et al., 2011;Rigonato-Oliveira et al., 2018), exhausted exercise has proven deleterious, leading to a panel of consequences, such as cardiac hypertrophy , and prone to develop upper respiratory tract infections (Fahlman and Engels, 2005;Walsh et al., 2011) and pulmonary interstitial edema or lung edema (Caillaud et al., 1995;McKenzie et al., 2005;Zavorsky, 2007). However, the study on the mechanism of pulmonary edema induced by exhausted exercise is limited so far, not to mention the protective measure. ...
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Background: Yu-ping-feng powder (YPF) is a compound traditional Chinese medicine extensively used in China for respiratory diseases. However, the role of YPF in alveolar-capillary barrier dysfunction remains unknown. This study aimed to explore the effect and potential mechanism of YPF on alveolar-capillary barrier injury induced by exhausted exercise. Methods: Male Sprague–Dawley rats were used to establish an exhausted-exercise model by using a motorized rodent treadmill. YPF at doses of 2.18 g/kg was administrated by gavage before exercise training for 10 consecutive days. Food intake-weight/body weight, blood gas analysis, lung water percent content, BALF protein concentration, morphological observation, quantitative proteomics, real-time PCR, and Western blot were performed. A rat pulmonary microvascular endothelial cell line (PMVEC) subjected to hypoxia was applied for assessing the related mechanism. Results: YPF attenuated the decrease of food intake weight/body weight, improved lung swelling and hemorrhage, alleviated the increase of lung water percent content and BALF protein concentration, and inhibited the impairment of lung morphology. In addition, YPF increased the expression of claudin 3, claudin 18, occludin, VE-cadherin, and β-catenin, attenuated the epithelial and endothelial hyperpermeability in vivo and/or in vitro , and the stress fiber formation in PMVECs after hypoxia. Quantitative proteomics discovered that the effect of YPF implicated the Siah2-ubiquitin-proteasomal pathway, Gng12-PAK1-MLCK, and RhoA/ROCK, which was further confirmed by Western blot. Data are available via ProteomeXchange with identifier PXD032737. Conclusion: YPF ameliorated alveolar-capillary barrier injury induced by exhausted exercise, which is accounted for at least partly by the regulation of cytoskeleton.
... AT reduces inflammation by presenting multiplied physiological benefits such as reducing toll-like receptors and NF-κB1 (p50) expression. It also increases lipolysis, down-regulates leukocyte migration, and enhances angiogenesis [50,51]. Based on the results, AT can suppress the mRNA expression of pro-inflammatory cytokines and enhance anti-inflammatory cytokines production. ...
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Background: Vitamin D (Vit D) supplementation and Aerobic Training (AT) exert several beneficial effects such as antioxidant and anti-inflammatory actions. The literature on the effects of AT and Vit D supplementation on the oxidative stress biomarkers and gene expression of inflammatory cytokines in patients with Type 2 Diabetes Mellitus (T2DM) is limited. The present study aimed to examine the effects of AT and Vit D supplementation on inflammation and oxidative stress signaling pathways in T2DM patients. Materials and methods: In this single-blinded, randomized, placebo-controlled trial, 48 men with T2DM (aged 35-50 years with Body Mass Index (BMI) of 25-30 kg/m2) were randomly allocated into four groups: AT+Vit D (n = 10); AT + placebo (AT; n = 10); Vit D (n = 10), and Control + placebo (C; n = 10). The eight-week AT program was executed for 20-40 min/day, at 60-75% of heart rate maximum (HRmax), for 3 days/wks. The Vit D group received 50,000 IU of Vit D supplement capsules per week for 8 weeks. The serum levels of oxidative stress biomarkers and gene expression of inflammatory cytokines in the Peripheral Blood Mononuclear Cells (PBMCs) were evaluated using the RT-PCR method. To analyze the data, paired t-tests and one-way analysis of variance and Tukey's post hoc test were used at the significance level of P < 0.05. Results: The result shows that serum 25-OH-Vit D, total nitrite, Total Glutathione (GSH), Total Antioxidant Capacity (TAC), Superoxide Dismutase (SOD), Catalase (CAT), and Glutathione Peroxidase (GPX) increased; and insulin, Fasting Blood Glucose (FBG), Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), High Sensitivity C-Reactive Protein (hs-CRP), Malondialdehyde (MDA), glycated albumin, and Urinary 8-hydroxydeoxyguanine (8-OHdG) decreased significantly in all groups after 8 weeks, except for C. In addition, results of RT-PCR showed that AT+Vit D, Vit D, and AT significantly downregulated the gene expression of Tumor Necrosis Factor-Alpha (TNF-α), Interleukin-1 Beta (IL-1β), Mitogen-Activated Protein Kinases 1 (MAPK1), Nuclear Factor Kappa B (NF-κB) 1 (p50). It also upregulated Interleukin-4 (IL-4) gene expression, Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) in T2DM patients compared to the C. Conclusion: Additionally, the AT+Vit D group showed significantly lower insulin, FBG, HOMA-IR, hs-CRP, MDA, glycated albumin, urinary 8-OHdG, IL-1β, TNF-α, MAPK1, and NF-κB1 (p50) levels and significantly higher serum 25-OH-Vit D, total nitrite, GSH, TAC, CAT, SOD, GPX, IL-4, and PPAR-γ levels compared to the AT and Vit D groups. In T2DM patients, 8 weeks of AT+Vit D had a more significant impact on certain gene expressions related to inflammation and oxidative stress than Vit D or AT alone.
... One of the effects of exercise training is the induction of inflammation, which occurs to repair and remodel muscle tissue, aiming at organic homeostasis after a single or several sessions of exercise. However, the systematization of this practice results in a local and systemic anti-inflammatory status [30]. In the present study, the levels of inflammatory markers evaluated were unaltered. ...
... Various regular exercise training protocols are recommended as non-pharmacological therapies to reduce obesity-related disorders (20). The secretion of adipomyokines such as TGF-b1, myostatin, FST, IL-7, and decorin from the extracellular matrix of adipose or muscle tissue is regulated by exercise (12,21). ...
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Objective To determine the effects of different intensities of interval resistance training (IRT) protocols on the levels of select myokines (decorin, follistatin, myostatin, activin A, transforming growth factor beta-1 [TGF-β1]), and cardiometabolic and anthropometric measures in males with obesity. Methods Forty-four obese males (age: 27.5 ± 9.4 yr.; height: 165.4 ± 2.8 cm; weight: 97.9 ± 2.6 kg and BMI: 35.7 ± 4.3 kg/m ² ) were randomly assigned to one of four groups (n=11 per group): low-intensity interval resistance training (LIIRT), moderate-intensity interval resistance training (MIIRT), high-intensity interval resistance training (HIIRT) or control (C). The LIIRT group performed 10 exercises in 3 sets of 40% (20 repetitions), the MIIRT group performed 10 exercises in three sets of 60% (13 repetitions), and the HIIRT group performed 10 exercises in three sets of 80% (10 repetitions) of one maximum repetition (1RM), which were followed with active rest of 20% of 1RM and 15 repetitions. The resistance training groups exercised ~70 min per session, 3 days per week, for 12 weeks. Measurements were taken at baseline and after 12 weeks of exercise training. Results Baseline levels of myokines, cardiovascular risk factors, anthropometry, body composition, and cardio-respiratory fitness were not different between the four groups (p>0.05). The group x time interactions for decorin, activin A, follistatin, myostatin, and TGF-β1, total cholesterol (TC), triglyceride (TG), high-density cholesterol (HDL), low-density cholesterol (LDL), anthropometry, body composition, and cardio-respiratory fitness were statistically significant (p<0.05). There were increases in post-test values for decorin, follistatin, HDL (p<0.05) and decreases in TC, TG, TGF-β1, LDL, and myostatin levels in the LIIRT, MIIRT, and HIIRT groups compared to pretest values (p<0.05). Changes in fat mass, VO 2peak, HDL, TG, glucose, activin A, decorin were not significant in LIIRT compared to the control group, while changes in activin A, follistatin, and TFG-β1 levels were greater in HIIRT and MIIRT groups compared to the LIIRT group (p<0.05). Conclusion The LIIRT, MIIRT, and HIIRT protocols all produced beneficial changes in decorin, activin A, follistatin, myostatin, and TGF-β1 levels, and cardiometabolic risk factors, with greater effects from the MIIRT and HIIRT protocols compared to LIIRT.
Poor sleep and chronic fatigue are common in people with chronic stroke (i.e. ≥ 6 months post‐stroke). Exercise training is a viable, low‐cost therapy for promoting sleep and reducing fatigue; however, the effects of exercise on sleep and fatigue in people with chronic stroke are unclear. Thus, we conducted a systematic review ascertaining the effects of exercise on sleep and fatigue in people with chronic stroke. We systematically searched EMBASE, MEDLINE, AgeLine, the Cochrane Database of Systematic Reviews, CINAHL, SPORTDiscus, SCOPUS, and reference lists of relevant reviews for articles that examined the effects of exercise on sleep or fatigue in chronic stroke. Search results were limited to adults ≥ 18 years, randomized controlled trials, non‐randomized trials, and pre–post studies, which were published in English and examined the effects of exercise on sleep or fatigue in people with chronic stroke. We extracted study characteristics and information on the measurement of sleep and fatigue, and assessed study quality and risk of bias using the CONSORT criteria and Cochrane risk‐of‐bias tool, respectively. We found two studies that examined the effects of exercise on sleep, and two that examined the effects of exercise on fatigue. All studies reported positive effects of exercise training on sleep and fatigue; however, there were concerns of bias and study quality in all studies. There is preliminary evidence that exercise promotes sleep and reduces fatigue in people with chronic stroke; however, the extent to which exercise impacts these health parameters is unclear.
This study evaluated the scientific evidence on the acute effects of high-intensity interval training (HIIT) on biochemical, cardiovascular, and metabolic parameters in patients with diabetes mellitus. The research took place using two databases (PubMed and Google Scholar) with eligible studies conducted between 2010 and 2020, using the following keywords: (1) high-intensity training/exercise; (2) interval training/exercise; (3) HIIT/exercise; AND “diabetes”. Data extraction was then performed on the eligible studies through content analysis using the categories: author and year of publication; sample characteristics; methods and data collected; intervention protocol; and results found. Methodological quality was assessed using the PEDro scale. Fourteen studies were included, evaluating 168 people with diabetes (122/46 type 2/1) and 42 normoglycemic individuals, which evaluated markers such as capillary and fasting blood glucose, 24-h blood glucose profile, postprandial blood glucose, incidence, and prevalence of hyperglycemia, vascular function and pressure response and control of inflammatory markers. Physical exercise was found to have several acute beneficial effects on the health of the diabetic population, such as reduced capillary and postprandial blood glucose, blood glucose profile, and blood pressure. Moreover, HIIT seems to be a safe and effective alternative in glycemic control and associated factors, superior to continuous moderate-intensity training.
High intensity interval training (HIIT) has been shown to benefit patients with psoriatic arthritis (PsA). However, magnetic resonance (MR) imaging has uncovered bone marrow edema (BME) in healthy volunteers after vigorous exercise. The purpose of this study was to investigate MR images of the spine of PsA patients for changes in BME after HIIT. PsA patients went through 11 weeks of HIIT (N = 19, 4 men, median age 52 years) or no change in physical exercise habits (N = 20, 8 men, median age 45 years). We acquired scores for joint affection and pain and short tau inversion recovery (STIR) and T1-weighted MR images of the spine at baseline and after 11 weeks. MR images were evaluated for BME by a trained radiologist, by SpondyloArthritis Research Consortium of Canada (SPARCC) scoring, and by extraction of textural features. No significant changes of BME were detected in MR images of the spine after HIIT. This was consistent for MR image evaluation by a radiologist, by SPARCC, and by texture analysis. Values of textural features were significantly different in BME compared to healthy bone marrow. In conclusion, BME in spine was not changed after HIIT, supporting that HIIT is safe for PsA patients.
Conference Paper
Incidences of breast cancer, type 2 diabetes, and metabolic syndrome have increased over the past decades with the obesity epidemic, especially in industrialized countries. Insulin resistance, hyperinsulinemia, and changes in the signaling of growth hormones and steroid hormones associated with diabetes may affect the risk of breast cancer. We reviewed epidemiologic studies of the association between type 2 diabetes and risk of breast cancer and the available evidence on the role of hormonal mediators of an association between diabetes and breast cancer. The combined evidence supports a modest association between type 2 diabetes and the risk of breast cancer, which appears to be more consistent among postmenopausal than among premenopausal women. Despite many proposed potential pathways, the mechanisms underlying an association between diabetes and breast cancer risk remain unclear, particularly because the 2 diseases share several risk factors, including obesity, a sedentary lifestyle, and possibly intake of saturated fat and refined carbohydrates, that may confound this association. Although the metabolic syndrome is closely related to diabetes and embraces additional components that might influence breast cancer risk, the role of the metabolic syndrome in breast carcinogenesis has not been studied and thus remains unknown.
Macrophages are widely distributed immune system cells that play an indispensable role in homeostasis and defense. They can be phenotypically polarized by the microenvironment to mount specific functional programs. Polarized macrophages can be broadly classified in two main groups: classically activated macrophages (or M1), whose prototypical activating stimuli are IFNgamma and LPS, and alternatively activated macrophages (or M2), further subdivided in M2a (after exposure to IL-4 or IL-13), M2b (immune complexes in combination with IL-1beta or LPS) and M2c (IL-10, TGFbeta or glucocorticoids). M1 exhibit potent microbicidal properties and promote strong IL-12-mediated Th1 responses, whilst M2 support Th2-associated effector functions. Beyond infection M2 polarized macrophages play a role in resolution of inflammation through high endocytic clearance capacities and trophic factor synthesis, accompanied by reduced pro-inflammatory cytokine secretion. Similar functions are also exerted by tumor-associated macrophages (TAM), which also display an alternative-like activation phenotype and play a detrimental pro-tumoral role. Here we review the main functions of polarized macrophages and discuss the perspectives of this field.
Context Studies have shown an inverse relationship between exercise and risk of coronary heart disease (CHD), but data on type and intensity are sparse. Objective To assess the amount, type, and intensity of physical activity in relation to risk of CHD among men. Design, Setting, and Participants A cohort of 44452 US men enrolled in the Health Professionals' Follow-up Study, followed up at 2-year intervals from 1986 through January 31, 1998, to assess potential CHD risk factors, identify newly diagnosed cases of CHD, and assess levels of leisure-time physical activity. Main Outcome Measure Incident nonfatal myocardial infarction or fatal CHD occurring during the follow-up period. Results During 475755 person-years, we documented 1700 new cases of CHD. Total physical activity, running, weight training, and rowing were each inversely associated with risk of CHID. The RRs (95% confidence intervals [CIs]) corresponding to quintiles of metabolic equivalent tasks (METs) for total physical activity adjusted for age, smoking, and other cardiovascular risk factors were 1.0, 0.90 (0.78-1.04), 0.87 (0.75-1.00), 0.83 (0.71-0.96), and 0.70 (0.59-0.82) (P<.001 for trend). Men who ran for an hour or more per week had a 42% risk reduction (RR, 0.58; 95% CI, 0.44-0.77) compared with men who did not run (P<.001 for trend). Men who trained with weights for 30 minutes or more per week had a 23% risk reduction (RR, 0.77; 95% CI, 0.61-0.98) compared with men who did not train with weights (P=.03 for trend). Rowing for 1 hour or more per week was associated with an 18% risk reduction (RR, 0.82; 05% CI, 0.68-0.99). Average exercise intensity was associated with reduced CHD risk independent of the total volume of physical activity. The RRs (95% CIs) corresponding to moderate (4-6 MET's) and high (6-12 METs) activity intensities were 0.94 (0.83-1.04) and 0.83 (0.72-0.97) compared with low activity intensity (<4 ME Ts) (P=.02 for trend). A half-hour per day or more of brisk walking was associated with an 18% risk reduction (RR, 0.82; 95% CI, 0.67-1.00). Walking pace was associated with reduced CHD risk independent of the number of walking hours. Conclusions Total physical activity, running, weight training, and walking were each associated with reduced CHID risk. Average exercise intensity was associated with reduced risk independent of the number of MET-hours spent in physical activity.
Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.
Monocytes play a central role in the inflammatory disease atherosclerosis. CD14+CD16+ monocytes are considered proinflammatory monocytes, as they have an increased capacity to produce proinflammatory cytokines, such as TNF-alpha, and are elevated in various inflammatory diseases. We hypothesized that :patients with coronary artery disease (CAD) have increased levels of CD14+CD16+ monocytes, and that CD14+CD16+ monocytes are associated with inflammation markiers.We investigated CD14+CD16+ monocytes in 247 Patients with CAD and 61 control subjects using flow cytometry. In addition serum concentrations of TNF-alpha IL-6, and Hs-CRP w ere assessed. Patients with CAD had higher levels of CD 14+CD 16+ monocytes than controls (13.6% versus 11.4%; p<0.001). Logistic regression analysis including quartiles of CD 14+CD 16+ monocytes showed that CD 14+CD 16+ monocytes were associated with prevalence of CAD (OR 4.9,95% Cl 2.5-19.1, for subjects in the fourth quartile in comparison to subjects in the first quartile). The association between CD14+CD16+ monocytes and CAD remained independently significant after adjustment for most potential confounders (OR 5.0, 95% Cl 1.2-20.0). Serum concentrations of TNF-alpha were elevated in subjects within the highest cluartiles of CD 14+CD 16+ monocytes (p=0.018). Our study showed that increased numbers of CD 14+CD 16+ monocytes are associated with coronary atherosclerosis and TNF-alpha. In accordance, recent animal studies suggest a possibly important role of these monocytes in the development of atherosclerosis.