ArticlePDF AvailableLiterature Review

Interleukin-6 in acute exercise and training: What is the biological relevance?


Abstract and Figures

It is now recognized that contracting skeletal muscle may synthesize and release interleukin-6 (IL-6) into the interstitium as well as into the systemic circulation in response to a bout of exercise. Although several sources of IL-6 have been demonstrated, contracting muscles contributes to most of the IL-6 present in the circulation in response to exercise. The magnitude of the exercise-induced IL-6 response is dependent on intensity and especially duration of the exercise, while the mode of exercise has little effect. Several mechanisms may link muscle contractions to IL-6 synthesis: Changes in calcium homeostasis, impaired glucose availability, and increased formation of reactive oxygen species (ROS) are all capable of activating transcription factors known to regulate IL-6 synthesis. Via its effects on liver, adipose tissue, hypothalamic-pituitary-adrenal (HPA) axis and leukocytes, IL-6 may modulate the immunological and metabolic response to exercise. However, prolonged exercise involving a significant muscle mass in the contractile activity is necessary in order to produce a marked systemic IL-6 response. Furthermore, exercise training may reduce basal IL-6 production as well as the magnitude of the acute exercise IL-6 response by counteracting several potential stimuli of IL-6. Accordingly, a decreased plasma IL-6 concentration at rest as well as in response to exercise appears to characterize normal training adaptation.
Content may be subject to copyright.
Interleukin-6 in acute exercise and training: what is
the biological relevance?
Christian P. Fischer, MD PhD
Centre of Inflammation and Metabolism, Department of Infectious Diseases
and Copenhagen Muscle Research Centre, Rigshospitalet and Faculty of
Health Sciences, University of Copenhagen, Denmark
Running title: Interleukin-6 in acute exercise and training
Keywords: Cortisol; Cytokines; Inflammation; Glucose metabolism; Lipid
metabolism; Skeletal muscle
It is now recognized that contracting skeletal muscle may synthesize and release
interleukin-6 (IL-6) into the interstitium as well as into the systemic circulation in
response to a bout of exercise. Although several sources of IL-6 have been demon-
strated, contracting muscles contributes to most of the IL-6 present in the circula-
tion in response to exercise. The magnitude of the exercise-induced IL-6 response
is dependent on intensity and especially duration of the exercise, while the mode
of exercise has little effect. Several mechanisms may link muscle contractions to
IL-6 synthesis: Changes in calcium homeostasis, impaired glucose availability,
and increased formation of reactive oxygen species (ROS) are all capable of acti-
vating transcription factors known to regulate IL-6 synthesis. Via its effects on
liver, adipose tissue, hypothalamic-pituitary-adrenal (HPA) axis and leukocytes,
IL-6 may modulate the immunological and metabolic response to exercise. How-
ever, prolonged exercise involving a significant muscle mass in the contractile
activity is necessary in order to produce a marked systemic IL-6 response. Fur-
thermore, exercise training may reduce basal IL-6 production as well as the mag-
nitude of the acute exercise IL-6 response by counteracting several potential stim-
uli of IL-6. Accordingly, a decreased plasma IL-6 concentration at rest as well as
in response to exercise appears to characterize normal training adaptation.
(Exerc. Immunol. Rev. 12, 2006: 6-33)
Since the first study in 1991 (115), several studies have consistently reported that
the plasma interleukin-6 (IL-6) concentration increases in response to exercise
6 • Interleukin-6 in acute exercise and training
Address Correspondence to:
Christian P. Fischer, Department of Infectious Diseases, Rigshospitalet University Hospital
of Copenhagen, Blegdamsvej 9, section M7641, DK-2100 Copenhagen, Denmark
Phone: (+45) 3545 8609 / Fax: (+45) 3545 7644 / E-mail:
(Table 1 & Fig. 1). Although
the plasma concentration of
several other cytokines may
be affected by exercise, IL-6
increases more dramatically
than any other cytokine inves-
tigated to date (120, 126). But
what determines the magni-
tude and time course of the
increase of IL-6 with exer-
cise? What is the effect of
exercise training on IL-6?
And what is the possible bio-
logical relevance of IL-6 in
acute and chronic physical
activity? These are some of
questions addressed in this
Two decades ago, IL-6
was first sequenced and
described as a cytokine facili-
tating the differentiation of B-
lymphocytes into immu-
noglobulin-secreting plasma
cells (55, 56). Later, several
other immunological proper-
ties was ascribed to this
pleiotropic cytokine, which
received its present name in
1987 (139). IL-6 belongs to a
family of cytokines that also
includes leukemia inhibitory
factor, interleukin-11, ciliary
neurotrophic factor, car-
diotrophin-1, and oncostatin
M. In addition to structural
similarities, these cytokines
share the gp130 receptor sub-
unit (76).
Transcription and trans-
lation of the human gene
encoding IL-6 – consisting of
a ~5 kilobase long sequence
containing 5 exons located on
chromosome 7 (155) – leads
to the synthesis of a propep-
tide containing 212 amino
acids, which is cleaved in
Interleukin-6 in acute exercise and training • 7
Fig. 1. Effect of mode and duration of exercise on
post-exercise plasma IL-6.
Different modes of exercise (dynamic knee-extensor,
bicycling, running, eccentric) and the corresponding
increase in plasma IL-6 (fold change from pre-exercise
level), based on the 67 exercise trials listed in Table 1 as
well as 7 trials representing various eccentric exercise
protocols (17, 53, 90, 144, 182, 194). Accordingly, the
graphs represent approximately 800 subjects. Each dot
represents one exercise trial, while the corresponding
bars show geometric means with 95% confidence inter-
vals (A). The overall log
linear relation (straight
solid line) between exercise duration and increase in
plasma IL-6 (fold change from pre-exercise level) indi-
cates that 51% of the variation in fold plasma IL-6
increase can be explained by the duration of exercise (B).
order to obtain the mature IL-6 peptide containing 184 amino acids (56). Interest-
ingly, a variant IL-6 peptide lacking the sequence encoded by exon II – thus
unable to signal via the gp130 receptor – may be released from stimulated lym-
phocytes and monocytes in concert with the full-length IL-6 (74). Further post-
translational modifications include varying degrees of glycosylation and phos-
8 • Interleukin-6 in acute exercise and training
Exercise mode
Knee-extensor Bicycling Running
n Duration
(fold change)
Ref n Duration
(fold change)
Ref n Duration
(fold change)
7 3.0 3 (38) 9 0.4 1 (33) 12 0.2 1 (195)
7 0.8 3 (52) 9 0.3 1 (188) 19 6.0 4 (30)
7 3.0 6 (127) 16 0.7 1 (96) 7 1.0 4 (113)
6 3.0 11 (71) 7 1.0 2 (12) 8 1.5 4 (178)
7 3.0 12 (37) 17 1.0 2 (186) 6 9.1 6 (132)
6 3.0 15 (168) 6 2.0 2 (59) 8 1.5 8 (179)
6 5.0 19 (172) 9 0.5 2 (17) 30 2.5 8 (102)
7 5.0 36 (165) 8 1.0 2 (87) 7 1.0 9 (163)
9 1.5 2 (86) 12 0.9 9 (114)
7 0.3 2 (42) 10 1.6 10 (159)
7 0.3 2 (42) 16 3.0 10 (107)
8 0.4 2 (33) 10 1.5 20 (134)
8 1.5 2 (177) 10 2.5 25 (119)
6 2.0 3 (59) 13 9.8 28 (108)
11 1.5 3 (181) 7 9.9 29 (110)
6 0.8 3 (189) 7 2.5 29 (170)
8 2.0 4 (11) 9 2.5 30 (169)
8 1.0 5 (89) 50 4.5 42 (112)
7 1.0 5 (163) 18 3.7 43 (21)
9 1.0 5 (146) 6 3.0 50 (84)
7 1.5 6 (164) 10 2.5 52 (109)
6 2.0 8 (31) 16 3.3 63 (121)
18 3.0 8 (128) 10 2.6 80 (175)
8 1.0 9 (118) 18 3.5 88 (18)
8 2.0 11 (60) 10 3.5 92 (183)
8 3.0 13 (69) 16 2.5 109 (176)
15 2.5 16 (106) 60 26.3 126 (111)
6 2.0 20 (162) 10 3.5 128 (120)
10 2.5 24 (109)
6 3.0 26 (117)
8 2.0 38 (47)
Table 1. Effect of acute exercise on plasma IL-6 in humans.
Shown is the relation between exercise mode (dynamic knee-extensor, bicycling, and run-
ning), exercise duration, and plasma IL-6 increase (fold change from pre-exercise level). In
studies investigating the effect of an intervention on the IL-6 response to exercise, e.g. car-
bohydrate supplementation, only the result from the control group (exercise without inter-
vention) is presented. Hence, the n value may be lower than the n value presented in the
original study.
phorylation, and several isoforms ranging from 21-30 kDa have been described
(7, 46, 51, 95). Whether the biological effects in vivo of these isoforms differ is
not established.
The plasma IL-6 concentration is ~1 pg/ml or even lower in resting healthy
subjects (17, 121). In contrast, the plasma IL-6 concentration may reach 10000
pg/ml in response to severe systemic infections (40). Less dramatic increases of
plasma IL-6 are found in numerous inflammatory and infectious diseases. A path-
ogenic role for IL-6 in the development of the metabolic syndrome has been sug-
gested, in part because the presence of a chronic low-level increase of plasma IL-
6 (usually <10 pg/ml) is associated with obesity (6), low physical activity (36,
123), insulin-resistance (13), type 2 diabetes (67), cardiovascular disease (39) and
may serve as a predictor of mortality (15).
Downstream signaling requires that IL-6 binds to the heterodimeric receptor
complex consisting of the ubiquitously expressed gp130 receptor and the specific
receptor IL-6Rα (50). This event triggers tyrosine-phosphorylation of gp130 by
Janus-activated kinases (Jak) on the intracellular domain, whereby at least two
distinct signalling pathways are activated: 1) the signal transducers and activators
of transcription (STAT) 1 and 3, and 2) the mitogen-activated protein kinases
(MAPK) (49). The two pathways are characterized by distinct effects; thus, the
effect of IL-6 may vary in different tissues depending on the balance between the
two pathways (54). A negative feedback mechanism of STAT activation involves
transcription and translation of the suppressor of cytokine signaling 3 (SOCS3).
Following exercise, the basal plasma IL-6 concentration may increase up to 100
fold, but less dramatic increases are more frequent (Table 1, Fig. 1A). Thus, the
8000-fold increase of plasma IL-6 following a 246 km “Spartathlon” race (92)
represents an atypical and extreme response. Of note, the exercise-induced
increase of plasma IL-6 is not linear over time; repeated measurements during
exercise show an accelerating increase of the IL-6 in plasma in an almost expo-
nential manner (37, 119, 172). Furthermore, the peak IL-6 level is reached at the
end of the exercise or shortly thereafter (37, 119), followed by a rapid decrease
towards pre-exercise levels.
Where does the exercise-induced IL-6 come from?
Importantly, the contracting skeletal muscle per se appears to be one of the main
sources of the IL-6 in the circulation in response to exercise: In resting human
skeletal muscle, the IL-6 mRNA content is very low, while small amounts of IL-6
protein predominantly in type I fibers may be detected using sensitive immuno-
histochemical methods (137). In response to exercise, an increase of the IL-6
mRNA content in the contracting skeletal muscle is detectable after 30 minutes of
exercise, and up to 100-fold increases of the IL-6 mRNA content may be present
at the end of the exercise bout (71, 168). Recently, further evidence that contract-
ing muscle fibers themselves are a source of IL-6 mRNA and protein has been
achieved by analysis of biopsies from the human vastus lateralis using in situ
hybridization and immunohistochemistry (58, 128). In addition, assessment of the
Interleukin-6 in acute exercise and training • 9
interstitial IL-6 concentration using microdialysis indicates that the concentration
of IL-6 within the contracting skeletal muscle may be 5-100 fold higher than the
levels found in the circulation (84, 147). Accordingly, IL-6 appears to accumulate
within the contracting muscle fibers as well in the interstitium during exercise.
However, it has been the simultaneous measurement of arterio-venous IL-6 con-
centrations and blood flow across the leg that has demonstrated that large
amounts of IL-6 can be released from the exercising leg (172). In the same study,
the authors also estimated that the net release from the exercising leg could
account for the systemic increase of plasma IL-6, assuming that IL-6 is distrib-
uted in the extracellular compartment and that IL-6 content in blood is the same in
plasma and the cellular fraction. Since IL-6 appears to be transported solely in the
non-cellular fraction of the blood (20), the net release of IL-6 from the exercising
leg probably was overestimated. Yet, a simpler approach based on the close log-
log linear relationship between recombinant human IL-6 (rhIL-6) dose and result-
ing steady state plasma IL-6 concentration (Fig. 2) supports the concept that IL-6
released from the exercising limb may account for systemic plasma IL-6 increase
following exercise: At the end of the exercise, the average release of IL-6 from the
contracting leg was 15 ng/min, while the systemic plasma IL-6 concentration was
14 pg/ml (172). Based on the dose-response relationship, the expected systemic
plasma IL-6 concentration corresponding to an IL-6 dose of 15 ng/min is 16
pg/ml (antilog
[1.05 · log
[15 ng/ml] + 0.07]), which corresponds well to the
observed value.
However, although IL-6 released from the contracting muscles may account
for most of the IL-6 found in the circulation, other studies have demonstrated that
skeletal muscle is not the sole source of exercise-induced IL-6. Using oral supple-
mentation with vitamins C and E for 4 weeks, the IL-6 net release from the exer-
cising legs was almost blocked completely, yet the systemic increase of plasma
IL-6 was only reduced by 50% (37). Very high concentrations of IL-6 along the
Achilles’ tendon has been detected using microdialysis in response to prolonged
running (84), but since the muscle mass involved in exercise is much higher than
the mass comprised by tendons, the mutual contribution of peritendinous versus
muscle-derived IL-6 to the systemic IL-6 is unclear. In addition, a small net
release of IL-6 from the internal jugular vein has been reported, suggesting that
the central nervous system may contribute to the IL-6 found in the circulation
(118). In contrast, a contribution from peripheral blood mononuclear cells to the
IL-6 found in the circulation of healthy subjects is detected consistently neither at
rest nor in response to exercise (121, 162, 186, 189). The adipose tissue may con-
tribute markedly to IL-6 in the circulation at rest (98, 160), but measurement of
arterio-venous plasma IL-6 differences across the abdominal subcutaneous adi-
pose tissue bed shows that this compartment does not contribute to the exercise-
induced IL-6 in the circulation until the recovery phase (88). However, since
almost any cell type may synthesize IL-6 upon adequate stimulation (3), further
studies may discover other sites contributing to the IL-6 in the circulation in
response to exercise.
How is the exercise-induced IL-6 response regulated?
Overall, the combination of mode, intensity and duration of the exercise deter-
mines the magnitude of the exercise-induced increase of plasma IL-6. However,
10 • Interleukin-6 in acute exercise and training
Interleukin-6 in acute exercise and training • 11
although it was suggested that the IL-6 response was related to muscle damage
(17), it now has become clear that eccentric exercise is not associated with more
marked increases of plasma IL-6 than compared to exercise involving concentric
muscle contractions (Fig 1A). Thus, muscle damage is not required in order to
increase plasma IL-6 during exercise. Rather, eccentric exercise may result in a
delayed peak and a slower decrease of plasma IL-6 during recovery (53, 90, 194).
In contrast, the IL-6 response is sensitive to the exercise intensity (122),
which again indirectly represents the muscle mass involved in the contractile
activity. Since contracting skeletal muscle per se is an important source of IL-6
found in the plasma (37, 172), it is therefore not surprising that exercise involving
a limited muscle mass, e.g. the muscles of the upper extremities, may be insuffi-
cient in order to increase plasma IL-6 above pre-exercise level (8, 57, 116). In
contrast, running – which involves several large muscle groups – is the mode of
exercise where the most dramatic plasma IL-6 increases have been observed
(Table 1, Fig. 1A).
Regardless, exercise duration is the single most important factor determining
the post-exercise plasma IL-6 amplitude (Table 1, Fig. 1B); more than 50% of the
variation in plasma IL-6 following exercise can be explained by exercise duration
alone (P < 10
). Since exercise at high intensity often is associated with shorter
duration of the exercise and vice versa, the relationship between the plasma IL-6
increase and the duration may be even more pronounced if adjusted for the exercise
intensity. In accordance, 6 minutes of maximal rowing ergometer exercise may
increase plasma IL-6 two-fold (105), but more than 10-fold increases of plasma IL-6
has not been observed in response to exercise lasting less than
1 h (Fig. 1B). Based on the log-log linear relationship between time and fold increase
of plasma IL-6 (Fig. 1B), a 10-fold increase of plasma IL-6 requires exercise for 1.9
h (95% confidence interval, CI, 1.6 - 2.9 h, P < 0.0001) of exercise, while a 100-fold
increase of plasma IL-6 requires exercise lasting 6.0 h (CI 4.5 - 8.1 h, P < 0.0001).
This relationship is remarkably insensitive to the mode of exercise, although the
highest increases of plasma IL-6 generally are found in response to running.
, increase; , decrease; , no effect of the intervention.
Intervention Effect on exercise-induced IL-6 References
Reduction of pre-exercise glycogen content Muscle IL-6 mRNA
Plasma IL-6
(24, 71, 171)
Supplementation with carbohydrates Muscle IL-6 mRNA
Plasma IL-6
(37, 179, 189)
Hyperglycemia in Type 1 diabetes Plasma IL-6 (42)
Nicotinic acid (inhibits lipolysis) Muscle IL-6 mRNA
Adipose tissue IL-6 mRNA
Plasma IL-6
Hot environment Plasma IL-6 (164)
Indomethacin (NSAID) Plasma IL-6 (143)
supplementation to COPD patients Plasma IL-6 (188)
Supplementation with antioxidants Muscle IL-6 mRNA
Plasma IL-6
(37, 179, 189)
Table 2. Some interventions influencing the exercise-induced IL-6 response.
12 • Interleukin-6 in acute exercise and training
What mechanisms may explain why contractile activity leads to increased
synthesis of IL-6? Since IL-6 is synthesized and released only from the contract-
ing muscles and not from the resting muscles exposed to the same hormonal
changes (66, 172), circulating systemic factors alone does not explain why con-
tracting muscles synthesize and release IL-6. Instead, local factors seem neces-
sary, although systemic factors may modulate the response.
The promoter region of the IL-6 gene contains binding sites for the nuclear
factor kappa B (NF-κB) and nuclear factor interleukin-6 (NFIL6) (93). Additional
transcription factors such as the nuclear factor of activated T cells (NFAT) (1) and
heat shock factors 1 and 2 (HSF1 and HSF2) (141) may contribute to the activa-
tion of IL-6 gene transcription. In vitro, calcium activates both NFAT and NF-κB
(29, 83), and incubation of muscle cell cultures with a calcium ionophore (iono-
mycin) increases IL-6 secretion in a p38 MAPK dependent manner (24). Human
studies have shown increased total and nuclear content of phosphorylated p38
MAPK, but unaltered nuclear content of NFAT in muscle biopsies after 1 h of
bicycling (97), while mRNA content of calcineurin A – which is involved in calci-
um signalling – is increased in muscle biopsies 6 h post 3 h of knee-extensor exer-
cise (136). Activation of NF-κB has been demonstrated in rat skeletal muscle after
exercise (65), but not consistently in humans (97). Noteworthy, NF-κB is a redox-
sensitive transcription factor (154) that may be activated by reactive oxygen
species (ROS). Increased ROS formation in exercising skeletal muscle following
exercise has been demonstrated directly in animals (27, 63) and indirectly in
humans (4). In vitro, murine skeletal myotubes release IL-6 when exposed to
oxidative stress in a NF-κB-dependent way (81). In addition, supplementation
with different antioxidants attenuates the systemic increase of IL-6 in response to
exercise (179, 189). Using arterio-venous differences of IL-6 across the leg, we
observed that the reduced systemic increase of IL-6 during exercise was due to an
almost complete inhibition of the net leg release of IL-6 in the group pre-treated
with vitamin C and E for 4 weeks (37). The observation that indomethacin – a
member of the non-steroid anti-inflammatory drugs (NSAID), which are known
to inhibit NF-κB activity – reduces the exercise-induced increase of IL-6 further
supports that NF-κB is likely to serve as a link between contractile activity and
IL-6 synthesis (80, 143). On the other hand, increased oxidative stress, as well as
low glucose availability, low glycogen content, catecholamines, increased intra-
cellular calcium levels, hyperthermia, ischemia-reperfusion are all features of
exercise capable of inducing heat shock proteins (HSPs) (9, 22, 34, 125, 190,
193), which may in turn activate IL-6 synthesis via HSF1 and HSF2 (141).
Accordingly, several regulators of IL-6 transcription are likely to be activated by
an altered intramuscular milieu in response to exercise (Fig. 4). This point of view
is supported by the various interventions that have demonstrated an effect on the
exercise-induced IL-6 response (Table 2). For instance, reduction of intramuscu-
lar glycogen content prior to exercise results increased accumulation of IL-6
mRNA within the contracting muscle as well as increased release of IL-6 from the
contracting muscle (24, 71, 171). This effect of glycogen reduction on the exer-
cise-induced IL-6 response may be mediated through activation of p38 MAPK
(24) and AMPK (89). In contrast, supplementation with carbohydrates during
exercise inhibits the exercise-induced increase of IL-6 in plasma, whereas IL-6
mRNA expression within the contracting muscle is unaffected (32, 102, 109,
163). While glucose availability may interfere with IL-6 gene expression through
AMPK (2), other mechanisms regulating IL-6 at a posttranslational level appear
to exist.
To make it even more complex, IL-6 appears to be capable of enhancing its
own transcription (72), which may partly explain the almost exponential increase
of IL-6 towards the end of exercise (Fig. 3). However, it should be noted that the
IL-6 released into the circulation is cleared very quickly, thus the ‘area under the
curve’ for plasma IL-6 in response is limited in particular in response to short
bouts of exercise (Fig. 3). In mice, the halflife of
I-labelled IL-6 in the circula-
tion is 2 minutes (99), which is accordance with the rapid decline of plasma IL-6
following rhIL-6 infusion from human studies (187). Most of the IL-6 is cleared
by the kidneys and the liver (31, 99).
What are the effects of IL-6 in acute exercise?
Exercise is known to cause major physiological, hormonal, metabolic, and
immunological effects. The question is whether exercise-induced IL-6 mediates
some of these effects. Of note, IL-6 may act locally within the contracting muscle
during exercise or within the adipose tissue during recovery, while most other
cells and target organs are exposed only to IL-6 released into the systemic circula-
tion. Regarding the systemic effects of IL-6, the dose-response relationship and
timing has to be considered. First, it should be noted that marked increases of
plasma IL-6 only occur if the exercise involves a considerable muscle mass work-
ing for a considerable amount of time at a considerable intensity. Otherwise, a
systemic IL-6 increase may be small or absent. Regardless, the exercise-induced
peak plasma IL-6 concentration will usually not exceed 100 pg/ml. Second, the
peak plasma IL-6 concentration occurs at the cessation of the exercise (or shortly
after), thus the systemic effects induced by IL-6 are for the most part expected to
occur during recovery from exercise.
Metabolic and hormonal effects of exercise-induced IL-6. Whole body oxy-
gen consumption and carbondioxide production increases in response to rhIL-6
infusion in the postabsorptive state as well as during a euglycemic hyperinsuline-
mic clamp (19, 184). This increase in energy turnover may occur without signifi-
cant changes in body temperature, though a moderate increase in body tempera-
ture – which occurs when the plasma IL-6 concentration is 300 pg/ml or higher
(174, 184, 185) – may per se be associated with an augmented energy turnover.
However, since a relatively high plasma IL-6 concentration apparently is required
in order to increase body temperature, it seems unlikely that the systemic increase
of IL-6 in response to exercise modulates metabolism through changes in body
In rats, IL-6 injection may deplete hepatic glycogen content (173). In vitro
and in vivo in animals, several studies have indicated that IL-6 interferes with
insulin-signalling in hepatocytes and liver tissue (68, 77, 78, 156, 157), whereby
hepatic glucose output may increase. However, even marked elevations of plasma
IL-6 has little effect on glucose metabolism in resting humans: In subjects both
with and without type 2 diabetes, an acute elevation of plasma IL-6 has no effect
glucose rate of appearance (R
), glucose disappearance (R
) or plasma glucose in
the postabsorptive state (133, 167). When combined with a euglycemic hyperin-
sulinemic clamp, an acute increase of plasma IL-6 to ~50 pg/ml has no effect on
Interleukin-6 in acute exercise and training • 13
plasma glucose, glucose
or R
(82), while an
acute increase of plasma
IL-6 to ~200 pg/ml
increases glucose R
glucose oxidation (19).
However, a much lower
increase of plasma IL-6
increases both glucose R
and R
during exercise
(35). The mechanism
behind the apparent dis-
crepancy between the
effect of IL-6 at rest and
during exercise is
unknown, but the presence
of additional “exercise
cofactors” capable of mod-
ulating the effect of IL-6
has been suggested (35).
Alternatively, the effect of
IL-6 on glucose metabo-
lism is only detectable
when glucose fluxes are
high as in response to
exercise or insulin stimula-
tion. Accordingly, a sys-
temic increase IL-6 in
response to exercise may
augment hepatic glucose output, while other tissues increase the uptake of glucose,
whereby the plasma glucose concentration is unaffected. Thus, it is possible that the
enhanced hepatic output is balanced by increased glucose uptake in the contracting
skeletal muscle during exercise. However, conflicting results regarding the effect of
IL-6 on glucose uptake in skeletal muscle exist: In mice, IL-6 decreases insulin-
mediated glucose uptake in skeletal muscle (75), while L6 myotubes exposed to IL-
6 in vitro demonstrate increased insulin-sensitivity (19).
Infusion of rhIL-6 increases lipolysis and fat oxidation after 2 h in healthy
subjects (187) and in subjects with type 2 diabetes (133). The lipolytic effect of
IL-6 is also observed in cultured adipocytes, suggesting a direct effect of IL-6 on
adipose tissue (133). Increased IL-6 mRNA content in the adipose tissue is
observed in response to exercise (69), and this increase appears to be mediated by
catecholamines (73). If the IL-6 mRNA is translated into protein, an additive
effect together with the IL-6 derived from the circulation is possible. Accordingly,
IL-6 and adrenaline may enhance the lipolytic capacity of each other in response
to exercise. As for the liver, the effect of IL-6 in adipocytes may partly be due to a
decrease in insulin-signalling (148, 158). Although adipose tissue mRNA expres-
sion of the hormone-sensitive lipase (HSL) is increased by rhIL-6 infusion, the
corresponding HSL protein is not affected (192).
14 • Interleukin-6 in acute exercise and training
Fig. 2. Dose-response curve for rhIL-6.
Shown is the plasma IL-6 concentration in response to dif-
ferent infusion rates of rhIL-6 diluted in saline containing
human albumin. The equation describes the log10-log10
linear regression (straight solid line). The light grey circles
represent data from a pilot study, while the dark grey
squares represent published data: A, (72); B, (133); C,
(187). Although the shown dose-response relationship has
been established in resting subjects, it has been proven use-
ful also in exercise trials (35).
Does IL-6 affect other hormones, which in part may explain the apparent
metabolic effects of IL-6? Table 3 summarizes some of the effects of an acute
increase of plasma IL-6 on some major hormones in humans. IL-6 injection
increases adrenocorticotropic hormone (ACTH) in a corticotropin-releasing hor-
mone (CRH) dependent manner in rats (101), while injection of an anti-IL-6 anti-
body abrogate the endotoxin-induced increase of ACTH in mice (131). Since the
IL-6 receptor present in the human pituitary gland (48) and adrenal cortex (45),
alternative pathways by which IL-6 can stimulate cortisol release in humans may
exist. A dose-dependent relationship between the IL-6 and cortisol in humans has
been demonstrated (184). In fact, a consistent increase of cortisol has been report-
ed when plasma IL-6 is ~50 pg/ml or higher (Table 3). Conversely, the post-exer-
cise increase of cortisol is attenuated if the release of IL-6 from the exercising leg
is inhibited by supplementation with vitamins C and E (37). However, the
increase of cortisol by IL-6 is abrogated during a euglycemic hyperinsulinemic
clamp (19). Taken together, it seems likely that an exercise-induced systemic
increase of IL-6 may reach concentrations capable of inducing cortisol secretion,
although other factors contributing to an exercise-induced activation of the HPA
axis not should be excluded. Of note, an increase of cortisol may contribute fur-
ther to the increased lipolysis and hepatic glucose output induced by IL-6. Inter-
estingly, the increase of cortisol may be involved in a negative feedback regula-
tion of IL-6, at least when present in higher concentrations (124).
While cortisol is induced by even modest plasma IL-6 increases, somewhat
higher plasma IL-6 concentrations appear to be necessary in order to increase
plasma glucagon and growth hormone (GH) levels consistently (Table 3). During
exercise, a low-level increase of IL-6 has no effect on either glucagon or GH (35).
Plasma concentrations of both adrenaline and noradrenaline are increased when
plasma IL-6 is ~300 pg/ml or higher (187). In healthy subjects, even very high IL-
6 doses have no acute effect on fasting postabsorptive plasma insulin levels (Table
3). However, IL-6 infusion may decrease plasma insulin in subjects with type 2
diabetes without concomitant changes in glucose turnover (133). Of note, the
increase of catecholamines and the decrease of insulin in response to exercise
comprise two highly potent stimuli for lipolysis (28, 64), while GH and cortisol
may further enhance the lipolysis (43, 151). Accordingly, IL-6 per se may induce
lipolysis but more likely IL-6 may stimulate lipolysis in concert with cate-
cholamines and cortisol. In type 2 diabetes, an additional decrease of plasma
insulin may contribute to the lipolytic effect of IL-6 (133).
Immunoregulatory effects of exercise-induced IL-6. In humans, infusion of
rhIL-6 increases plasma cortisol, IL-1 receptor antagonist (IL-1ra), IL-10, soluble
TNF-α receptors (sTNF-R), and C-reactive protein (CRP) (149, 166, 180). Con-
versely, the increase of cortisol, IL-1ra and CRP after exercise is abrogated if the
release of IL-6 from the contracting muscles is reduced by supplementation with
antioxidants (37), suggesting that IL-6 from the contracting skeletal muscle in
part accounts for the increase of cortisol, IL-Ira and CRP.
The anti-inflammatory properties of cortisol are well characterized (5). In
response to rhIL-6 infusion, a significant increase of cortisol occurs within one
hour (166). While moderate exercise increase number as well as antimicrobial
capacity of the neutrophils in the circulation, intense exercise is associated with a
reduced antimicrobial capacity of the neutrophils (126), which is likely to be
Interleukin-6 in acute exercise and training • 15
mediated by cortisol (91). In addition, cortisol may reduce the number of lympho-
cytes by enhancing the apoptosis. Thus, higher systemic increases of IL-6 – as
observed after prolonged intense exercise – may in part be responsible for the
changes in leukocyte subpopulations and antimicrobial capacity.
IL-1ra is a cytokine produced primarily by macrophages, but a further con-
tribution may come from hepatocytes and monocytes (41, 180). IL-1ra attenuates
the effect of the pro-inflammatory cytokine IL-1 by reducing the signal transduc-
tion through the IL-1 receptor (41). Plasma IL-1ra is increased after rhIL-6 infu-
sion for one hour (166). In contrast to IL-1ra, IL-10 is capable of inhibiting the
LPS-stimulated production of several pro-inflammatory cytokines including
TNF-α, IL-1α and IL-1β (100, 140). The anti-inflammatory effect of IL-10 is
exerted at both the transcriptional and posttranslational level (10, 191). Lympho-
cytes and monocytes are the primary sources of IL-10, which increases in plasma
in response to rhIL-6 infusion for 2 hours (166).
IL-6 infusion also induces a delayed increase of CRP from the liver via acti-
vation of the STAT3 pathway (166, 196). CRP was originally characterized as an
acute phase protein involved in precipitation of the somatic C-polysaccharide of
Streptococcus pneumoniae (130). Whether CRP has pro-inflammatory effects or
not is being debated (129). When purified adequately, even high doses of recom-
binant CRP do not induce a pro-inflammatory response (129). Rather, CRP may
contribute to the increase of plasma IL-1ra during late recovery from exercise by
enhancing the release of IL-1ra from monocytes (142).
Furthermore, while the pro-inflammatory cytokine TNF-α can stimulate IL-
6 production (138), IL-6 does not stimulate the production of TNF-α (166).
Rather, IL-6 attenuates the LPS-stimulated production of TNF-α in cultured
monocytes (153) as well as in vivo in humans (161), while treatment with anti-IL-
6 antibodies augment the TNF-α response following challenge with staphylococ-
cal enterotoxin B in mice (94). In addition, IL-6 may attenuate the effect of TNF-
α by induction of sTNF-R (180).
Taken together, the release of IL-6 from the contracting muscles may facili-
tate a broad anti-inflammatory response via effects on liver as well as on different
leukocyte subpopulations.
Exercise training involves multiple adaptations including increased pre-exercise
skeletal muscle glycogen content, enhanced activity of key enzymes involved in
the beta-oxidation (152), increased sensitivity of adipose tissue to adrenaline-
stimulated lipolysis (26), increased oxidation of intramuscular triglycerides (135),
whereby the capacity to oxidize fat is increased (61, 150). As a consequence, the
trained skeletal muscle is less dependent on plasma glucose and muscle glycogen
as substrate during exercise (135).
Several epidemiological studies have reported a negative association
between the amount of regular physical activity and the basal plasma IL-6 levels:
the more physical active, the lower basal plasma IL-6 (23, 25, 123). Basal plasma
IL-6 is closer associated with physical inactivity than other cytokines associated
with the metabolic syndrome (36).
16 • Interleukin-6 in acute exercise and training
The epidemiologi-
cal data are supported by
findings from interven-
tion studies, although
these produce less con-
sistent results. Basal lev-
els of IL-6 are reduced
after training in patients
with coronary artery dis-
ease (44). Aerobic train-
ing of adults aged 64 ys
or more for 10 months
also decreases basal
plasma IL-6 (79). In
severely obese subjects,
the combination of a
hypocaloric diet and reg-
ular physical activity for
15 weeks reduces not
only plasma IL-6, but
also the IL-6 mRNA
content in subcutaneous
adipose tissue and in
skeletal muscle (14). In
addition, athlete skiers
have lower basal plasma
IL-6 during the training
season than off-season
(145). However, others
have not observed
changes in basal IL-6
levels in response to
training (16, 85, 104).
At present, evidence that the exercise-induced increase of plasma IL-6 is
affected by training is limited. Using knee-extensor exercise, 7 healthy men
trained for 1 hour 5 times a week for 10 weeks (38). Before and after the training,
the participants performed knee-extensor exercise for 3 h at 50% of the maximal
workload. Due to a marked training response, the absolute workload was much
higher after training compared to pre-training. Despite this, the increase in IL-6
mRNA content by acute exercise was 76-fold before training but only 8 fold after
training. In addition, the exercise-induced increase of plasma IL-6 was similar
before and after training, although the absolute workload was increased by 44%
with training. Accordingly, it could be speculated that differences in training sta-
tus may explain why elderly subjects release the same amount of IL-6 as young
subjects from the leg during knee-extensor exercise at the exact same relative –
but half the same absolute – workload (127).
Noteworthy, while IL-6 appears to be down-regulated by training, the IL-6
receptor appears to be up-regulated: In response to exercise training, the basal IL-
Interleukin-6 in acute exercise and training • 17
Fig. 3. The effect of exercise duration and intensity on the
plasma IL-6 level.
Schematic presentation showing that in response to exercise,
plasma IL-6 increases in a non-linear fashion over time (37,
119, 172) and peaks shortly after the cessation of the exer-
cise (solid line). If the exercise intensity increases, plasma
IL-6 is likely to increase faster resulting in a higher peak
plasma IL-6 level (dotted line). If the exercise duration is
extended, the peak plasma IL-6 occurs later but is also aug-
mented (dashed line). From an “area under the curve” point
of view, the cumulative systemic effect of IL-6 in response to
exercise may accordingly be more prominent in response to
prolonged exercise compared to an intense but shorter bout
of exercise, even if the peak IL-6 values are similar.
6R mRNA content in trained skeletal muscle is increased by ~100% (70). Accord-
ingly, it is possible that the downregulation of IL-6 is partially counteracted by
enhanced expression of IL-6R, whereby the sensitivity to IL-6 is increased. How-
ever, it remains to be determined if the increased IL-6R mRNA content corre-
sponds to an increased expression of the IL-6R protein. Furthermore, it is not
known if the enhanced IL-6R expression following training occurs in several tis-
sues or only locally within the trained skeletal muscle. In the circulation, the IL-
6R concentration is affected neither by training nor acute exercise (70).
Thus, there is good evidence that low physical activity results in elevated
basal IL-6 levels, while a high level of physical activity results in low basal IL-6
levels. Yet, there is limited evidence indicating that the exercise-induced increase
of IL-6 in the contracting muscle as well as in the circulation is attenuated by
training. Since training adaptation includes changes known to counteract potential
stimuli for IL-6, it is, however, very likely that further studies will demonstrate
alterations in the exercise-induced IL-6 response by training.
Clearly, exercise may increase synthesis and subsequent release of IL-6 from con-
tracting muscles, and this release may induce multiple effects in multiple tissues.
IL-6 possesses somewhat catabolic features, indicated by the ability to increase
energy expenditure, increase lipolysis, increase fat oxidation, increase endoge-
nous glucose output (in part via reducing insulin-signalling in fat and liver), and
increase cortisol. On the other hand, this mobilization of glucose and FFA from
liver and fat to the circulation may result in enhanced substrate uptake by other
tissues, e.g., the contracting skeletal muscle. The apparent discrepancy between
tissues regarding the response to IL-6 may be due differences in downstream IL-6
signalling in different tissues. In addition, the IL-6 released from the contracting
muscles may induce an anti-inflammatory response reflected by increase of IL-
1ra, IL-10, CRP, and cortisol without concomitant increases in pro-inflammatory
18 • Interleukin-6 in acute exercise and training
, increase; , decrease; , not affected by rhIL-6; GH, growth hormone; A, adrenaline; NA, noradrenaline.
In response to rhIL-6 infusion, plasma insulin decreases in subjects with type 2 diabetes but not in healthy controls.
Plasma IL-6 level
Insulin Cortisol Glucagon GH A, NA References
< 50
(35, 59, 184,
(166, 167,
~200 /
(133, 192)
(167, 184,
185, 187)
(184, 185)
Table 3. Acute effects of rhIL-6 on hormone levels in humans.
The time and intensity required in order to accumulate IL-6 protein within
the contracting muscle are not well characterized. In contrast, duration of exercise
is the single most important factor that determines the magnitude of the systemic
IL-6 response. The longer duration of the exercise, the more pronounced the sys-
temic IL-6 response will be. Accordingly, short bouts of exercise or exercise at
low intensity are not likely to increase IL-6 to an extent where systemic effects of
IL-6 are expected. Independent of mode, exercise for less than one hour induces a
peak plasma IL-6 concentration below 10 pg/ml (< 10 fold increase from pre-
exercise level, Fig. 1B), and this for only a short period of time (Fig. 2). Several
studies have demonstrated that pre-exercise glycogen depletion accelerates the
exercise-induced IL-6 response, while carbohydrate supplementation reduces the
increase of plasma IL-6. Thus, reduced availability of substrates fuelling the mus-
Interleukin-6 in acute exercise and training • 19
Fig. 4. Possible effects of IL-6 released from contracting skeletal muscle in response to
Several mechanisms may link muscle contractions to IL-6 synthesis. Changes in calcium
homeostasis, impaired glucose availability, and increased formation of reactive oxygen
species (ROS) are all capable of inducing transcription factors regulating IL-6 gene tran-
scription. The synthesized IL-6 may act locally within the contracting skeletal muscle in a
paracrine manner or be released into the circulation, thus able to induce systemic effects. In
liver, the circulating IL-6 may increase hepatic glucose output and production of C-reactive
protein (CRP). In adipose tissue, IL-6 produced locally and IL-6 from the circulation in
concert may increase lipolysis. Via activation of the hypothalamic-pituitary-adrenal (HPA)
axis, the circulating IL-6 may stimulate cortisol release, which may further enhance the
lipolysis. In lymphocytes, macrophages, and monocytes, the circulating IL-6 may stimu-
late the production of IL-1ra and IL-10.
cle contractile activity appears to be one of the main triggers of IL-6 production.
To reduce substrate availability, glycogen stores in liver and muscle have to be
reduced markedly, which is process that takes time, although dependent on the
Low physical activity is associated with increased plasma IL-6 at rest. Exer-
cise training dramatically reduces the exercise-induced accumulation of IL-6
mRNA within the contracting skeletal muscle. Training adaptation also includes
increased glycogen content in the resting skeletal muscle and enhanced capacity
to oxidize fat, whereby the contracting muscle becomes less dependent on plasma
glucose as well as capable of performing more mechanical work before glycogen
levels are reduced critically. Accordingly, exercise training may counteract sever-
al potential stimuli of IL-6 production. Therefore, a low plasma IL-6 concentra-
tion at rest as well as in response to exercise appears to characterize the IL-6
response after training adaptation. Interestingly, the training-induced downregula-
tion of IL-6 may to some extent be compensated by an enhanced sensitivity to IL-
6, at least within the trained skeletal muscle.
1. Abbott KL, Loss JR, II, Robida AM and Murphy TJ. Evidence That Galpha q-
Coupled Receptor-Induced Interleukin-6 mRNA in Vascular Smooth Muscle
Cells Involves the Nuclear Factor of Activated T Cells. Mol Pharmacol 58: 946-
953, 2000.
2. Akerstrom TCA, Birk JB, Klein DK, Erikstrup C, Plomgaard P, Pedersen BK and
Wojtaszewski JFP. Oral glucose ingestion attenuates exercise-induced activation
of 5'-AMP-activated protein kinase in human skeletal muscle. Biochemical and
Biophysical Research Communications 342: 949-955, 2006.
3. Akira S, Taga T and Kishimoto T. Interleukin-6 in biology and medicine.
Advances in Immunology 54: 1-78, 1993.
4. Bailey DM, Young IS, McEneny J, Lawrenson L, Kim J, Barden J and Richardson
RS. Regulation of free radical outflow from an isolated muscle bed in exercising
humans. AJP - Heart and Circulatory Physiology 287: H1689-99, 2004.
5. Barnes PJ. Anti-inflammatory actions of glucocorticoids: molecular mechanisms.
Clin Sci (Lond) 94: 557-572, 1998.
6. Bastard JP, Jardel C, Bruckert E, Blondy P, Capeau J, Laville M, Vidal H and
Hainque B. Elevated levels of interleukin 6 are reduced in serum and subcuta-
neous adipose tissue of obese women after weight loss. J Clin Endocrinol Metab
85: 3338-3342, 2000.
7. Bauer J, Ganter U, Geiger T, Jacobshagen U, Hirano T, Matsuda T, Kishimoto T,
Andus T, Acs G and Gerok W. Regulation of interleukin-6 expression in cultured
human blood monocytes and monocyte-derived macrophages. Blood 72: 1134-
1140, 1988.
8. Bergfors M, Barnekow-Bergkvist M, Kalezic N, Lyskov E and Eriksson JW.
Short-term effects of repetitive arm work and dynamic exercise on glucose
metabolism and insulin sensitivity. Acta Physiologica Scandinavica 183: 345-
356, 2005.
9. Bergstedt K, Hu BR and Wieloch T. Initiation of protein synthesis and heat-shock
20 • Interleukin-6 in acute exercise and training
protein-72 expression in the rat brain following severe insulin-induced hypo-
glycemia. Acta Neuropathol (Berl) 86: 145-153, 1993.
10. Bogdan C, Paik J, Vodovotz Y and Nathan C. Contrasting mechanisms for sup-
pression of macrophage cytokine release by transforming growth factor-beta and
interleukin-10. J Biol Chem 267: 23301-23308, 1992.
11. Brenner IK, Natale VM, Vasiliou P, Moldoveanu AI, Shek PN and Shephard RJ.
Impact of three different types of exercise on components of the inflammatory
response. Eur J Appl Physiol 80: 452-460, 1999.
12. Brenner IKM, Castellani JW, Gabaree C, Young AJ, Zamecnik J, Shephard RJ
and Shek PN. Immune changes in humans during cold exposure: effects of prior
heating and exercise. J Appl Physiol 87: 699-710, 1999.
13. Bruun JM, Verdich C, Toubro S, Astrup AV and Richelsen B. Association
between measures of insulin sensitivity and circulating levels of interleukin-8,
interleukin-6 and tumor necrosis factor-alpha. Effect of weight loss in obese men.
Eur J Endocrinol 148: 535-542, 2003.
14. Bruun JM, Helge JW, Richelsen B and Stallknecht B. Diet and exercise reduce
low-grade inflammation and macrophage infiltration in adipose tissue but not in
skeletal muscle in severely obese subjects. Am J Physiol Endocrinol Metab 290:
E961-E967, 2006.
15. Bruunsgaard H. Effects of tumor necrosis factor-alpha and interleukin-6 in elder-
ly populations. Eur Cytokine Netw 13: 389-91, 2002.
16. Bruunsgaard H, Bjerregaard E, Schroll M and Pedersen BK. Muscle strength
after resistance training is inversely correlated with baseline levels of soluble
tumor necrosis factor receptors in the oldest old. J Am Geriatr Soc 52: 237-241,
17. Bruunsgaard H, Galbo H, Halkjaer-Kristensen J, Johansen TL, MacLean DA and
Pedersen BK. Exercise-induced increase in serum interleukin-6 in humans is
related to muscle damage. J Physiol (Lond) 499 ( Pt 3): 833-841, 1997.
18. Camus G, Poortmans J, Nys M, Deby-Dupont G, Duchateau J, Deby C and Lamy
M. Mild endotoxaemia and the inflammatory response induced by a marathon
race. Clin Sci (Lond) 92: 415-422, 1997.
19. Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG, Ramm G,
Prelovsek O, Hohnen-Behrens C, Watt MJ, James DE, Kemp BE, Pedersen BK
and Febbraio MA. Interleukin-6 Increases Insulin-Stimulated Glucose Disposal
in Humans and Glucose Uptake and Fatty Acid Oxidation In Vitro via AMP-Acti-
vated Protein Kinase. Diabetes 55: 2688-2697, 2006.
20. Castell JV, Geiger T, Gross V, Andus T, Walter E, Hirano T, Kishimoto T and
Heinrich PC. Plasma-Clearance, Organ Distribution and Target-Cells of Inter-
leukin-6 Hepatocyte-Stimulating Factor in the Rat. European Journal of Bio-
chemistry 177: 357-361, 1988.
21. Castell LM, Poortmans JR, Leclercq R, Brasseur M, Duchateau J and Newsholme
EA. Some aspects of the acute phase response after a marathon race, and the
effects of glutamine supplementation. Eur J Appl Physiol 75: 47-53, 1997.
22. Cavaliere F, D'Ambrosi N, Sancesario G, Bernardi G and Volonte C. Hypogly-
caemia-induced cell death: features of neuroprotection by the P2 receptor antago-
nist basilen blue. Neurochem Int 38: 199-207, 2001.
23. Cesari M, Penninx BWJH, Pahor M, Lauretani F, Corsi AM, Williams GR, Gural-
nik JM and Ferrucci L. Inflammatory Markers and Physical Performance in Older
Interleukin-6 in acute exercise and training • 21
Persons: The InCHIANTI Study. J Gerontol A Biol Sci Med Sci 59: M242-M248,
24. Chan MHS, McGee SL, Watt MJ, Hargreaves M and Febbraio MA. Altering
dietary nutrient intake that reduces glycogen content leads to phosphorylation of
nuclear p38 MAP kinase in human skeletal muscle: association with IL-6 gene
transcription during contraction. FASEB J 18: 1785-1787, 2004.
25. Colbert LH, Visser M, Simonsick EM, Tracy RP, Newman AB, Kritchevsky SB,
Pahor M, Taaffe DR, Brach J, Rubin S and Harris TB. Physical Activity, Exercise,
and Inflammatory Markers in Older Adults: Findings from The Health, Aging and
Body Composition Study. Journal of the American Geriatrics Society 52: 1098-
1104, 2004.
26. Crampes F, Beauville M, Riviere D and Garrigues M. Effect of physical training
in humans on the response of isolated fat cells to epinephrine. J Appl Physiol 61:
25-29, 1986.
27. Davies KJ, Quintanilha AT, Brooks GA and Packer L. Free radicals and tissue
damage produced by exercise. Biochem Biophys Res Commun 107: 1198-1205,
28. Divertie GD, Jensen MD, Cryer PE and Miles JM. Lipolytic responsiveness to
epinephrine in nondiabetic and diabetic humans. Am J Physiol Endocrinol Metab
272: E1130-E1135, 1997.
29. Dolmetsch RE, Xu K and Lewis RS. Calcium oscillations increase the efficiency
and specificity of gene expression. Nature 392: 933-936, 1998.
30. Drenth JP, Van Uum SH, Van Deuren M, Pesman GJ, Van der Ven-Jongekrijg J
and van der Meer JW. Endurance run increases circulating IL-6 and IL-1ra but
downregulates ex vivo TNF-alpha and IL-1 beta production. J Appl Physiol 79:
1497-1503, 1995.
31. Febbraio MA, Ott P, Nielsen HB, Steensberg A, Keller C, Krustrup P, Secher NH
and Pedersen BK. Hepatosplanchnic clearance of interleukin-6 in humans during
exercise. Am J Physiol Endocrinol Metab 285: E397-E402, 2003.
32. Febbraio MA, Steensberg A, Keller C, Starkie RL, Nielsen HB, Krustrup P, Ott P,
Secher NH and Pedersen BK. Glucose ingestion attenuates interleukin-6 release
from contracting skeletal muscle in humans. J Physiol 549: 607-612, 2003.
33. Febbraio MA, Steensberg A, Starkie RL, McConell GK and Kingwell BA. Skele-
tal muscle interleukin-6 and tumor necrosis factor-alpha release in healthy sub-
jects and patients with type 2 diabetes at rest and during exercise. Metabolism 52:
939-944, 2003.
34. Febbraio MA, Steensberg A, Walsh R, Koukoulas I, Van Hall G and Pedersen BK.
Reduced muscle glycogen availability elevates HSP72 in contracting human
skeletal muscle. J Physiol 538: 911-917, 2002.
35. Febbraio MA, Hiscock N, Sacchetti M, Fischer CP and Pedersen BK. Interleukin-
6 Is a Novel Factor Mediating Glucose Homeostasis During Skeletal Muscle
Contraction. Diabetes 53: 1643-1648, 2004.
36. Fischer CP, Berntsen A, Perstrup LB, Eskildsen P and Pedersen BK. Plasma lev-
els of IL-6 and CRP are associated with physical inactivity independent of obesi-
ty. Scandinavian Journal of Medicine and Science in Sports, 2006 (In Press).
37. Fischer CP, Hiscock NJ, Penkowa M, Basu S, Vessby B, Kallner A, Sjoberg LB and
Pedersen BK. Supplementation with vitamins C and E inhibits the release of inter-
leukin-6 from contracting human skeletal muscle. J Physiol 558: 633-645, 2004.
22 • Interleukin-6 in acute exercise and training
38. Fischer CP, Plomgaard P, Hansen AK, Pilegaard H, Saltin B and Pedersen BK.
Endurance training reduces the contraction-induced interleukin-6 mRNA expres-
sion in human skeletal muscle. Am J Physiol Endocrinol Metab 287: E1189-
E1194, 2004.
39. Fisman EZ, Benderly M, Esper RJ, Behar S, Boyko V, Adler Y, Tanne D, Matas Z
and Tenenbaum A. Interleukin-6 and the Risk of Future Cardiovascular Events in
Patients With Angina Pectoris and/or Healed Myocardial Infarction. Am J Cardiol
98: 14-18, 2006.
40. Friedland JS, Suputtamongkol Y, Remick DG, Chaowagul W, Strieter RM,
Kunkel SL, White NJ and Griffin GE. Prolonged elevation of interleukin-8 and
interleukin-6 concentrations in plasma and of leukocyte interleukin-8 mRNA lev-
els during septicemic and localized Pseudomonas pseudomallei infection. Infect
Immun 60: 2402-2408, 1992.
41. Gabay C, Smith MF, Eidlen D and Arend WP. Interleukin 1 receptor antagonist
(IL-1Ra) is an acute-phase protein. J Clin Invest 99: 2930-2940, 1997.
42. Galassetti PR, Iwanaga K, Pontello AM, Zaldivar FP, Flores RL and Larson JK.
Effect of prior hyperglycemia on IL-6 responses to exercise in children with type
1 diabetes. Am J Physiol Endocrinol Metab 290: E833-E839, 2006.
43. Galton DJ and Bray GA. Studies on lipolysis in human adipose cells. J Clin
Invest 46: 621-629, 1967.
44. Goldhammer E, Tanchilevitch A, Maor I, Beniamini Y, Rosenschein U and Sagiv
M. Exercise training modulates cytokines activity in coronary heart disease
patients. International Journal of Cardiology 100: 93-99, 2005.
45. Gonzalez-Hernandez JA, Bornstein SR, Ehrhart-Bornstein M, Spath-Schwalbe E,
Jirikowski G and Scherbaum WA. Interleukin-6 messenger ribonucleic acid
expression in human adrenal gland in vivo: new clue to a paracrine or autocrine
regulation of adrenal function. J Clin Endocrinol Metab 79: 1492-1497, 1994.
46. Gross V, Andus T, Castell J, Vom BD, Heinrich PC and Gerok W. O- and N-gly-
cosylation lead to different molecular mass forms of human monocyte inter-
leukin-6. FEBS Lett 247: 323-326, 1989.
47. Hagobian TA, Jacobs KA, Subudhi AW, Fattor JA, Rock PB, Muza SR, Fulco CS,
Braun B, Grediagin A, Mazzeo RS, Cymerman A and Friedlander AL. Cytokine
responses at high altitude: effects of exercise and antioxidants at 4300 m. Med
Sci Sports Exerc 38: 276-285, 2006.
48. Hanisch A, Dieterich KD, Dietzmann K, Ludecke K, Buchfelder M, Fahlbusch R
and Lehnert H. Expression of Members of the Interleukin-6 Family of Cytokines
and their Receptors in Human Pituitary and Pituitary Adenomas. J Clin
Endocrinol Metab 85: 4411, 2000.
49. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G and Schaper
F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation.
Biochem J 374: 1-20, 2003.
50. Heinrich PC, Behrmann I, Muller-Newen G, Schaper F and Graeve L. Inter-
leukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem
J 334 ( Pt 2): 297-314, 1998.
51. Helfgott DC, Tatter SB, Santhanam U, Clarick RH, Bhardwaj N, May LT and
Sehgal PB. Multiple forms of IFN-beta 2/IL-6 in serum and body fluids during
acute bacterial infection. J Immunol 142: 948-953, 1989.
52. Helge JW, Stallknecht B, Pedersen BK, Galbo H, Kiens B and Richter EA. The
Interleukin-6 in acute exercise and training • 23
effect of graded exercise on IL-6 release and glucose uptake in human skeletal
muscle. J Physiol 546: 299-305, 2003.
53. Hellsten Y, Frandsen U, Orthenblad N, Sjodin B and Richter EA. Xanthine oxi-
dase in human skeletal muscle following eccentric exercise: a role in inflamma-
tion. J Physiol 498 ( Pt 1): 239-248, 1997.
54. Hirano T, Ishihara K and Hibi M. Roles of STAT3 in mediating the cell growth,
differentiation and survival signals relayed through the IL-6 family of cytokine
receptors. Oncogene 19: 2548-2556, 2000.
55. Hirano T, Taga T, Nakano N, Yasukawa K, Kashiwamura S, Shimizu K, Nakajima
K, Pyun KH and Kishimoto T. Purification to homogeneity and characterization
of human B-cell differentiation factor (BCDF or BSFp-2). Proc Natl Acad Sci U
S A 82: 5490-5494, 1985.
56. Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Matsuda T, Kashiwamura
S, Nakajima K, Koyama K, Iwamatsu A and . Complementary DNA for a novel
human interleukin (BSF-2) that induces B lymphocytes to produce immunoglob-
ulin. Nature 324: 73-76, 1986.
57. Hirose L, Nosaka K, Newton M, Laveder A, Kano M, Peake J and Suzuki K.
Changes in inflammatory mediators following eccentric exercise of the elbow
flexors. Exerc Immunol Rev 10: 75-90, 2004.
58. Hiscock N, Chan MHS, Bisucci T, Darby IA and Febbraio MA. Skeletal
myocytes are a source of interleukin-6 mRNA expression and protein release dur-
ing contraction: evidence of fiber type specificity. FASEB J 18: 992-994, 2004.
59. Hiscock N, Fischer CP, Sacchetti M, Van Hall G, Febbraio MA and Pedersen BK.
Recombinant human interleukin-6 infusion during low intensity exercise does not
enhance whole body lipolysis or fat oxidation in humans. Am J Physiol
Endocrinol Metab 289: E2-7, 2005.
60. Hiscock N, Petersen EW, Krzywkowski K, Boza J, Halkjaer-Kristensen J and
Pedersen BK. Glutamine supplementation further enhances exercise-induced
plasma IL-6. J Appl Physiol 95: 145-148, 2003.
61. Holloszy JO and Booth FW. Biochemical Adaptations to Endurance Exercise in
Muscle. Ann Rev Physiol 38: 273-291, 1976.
62. Holmes AG, Watt MJ and Febbraio MA. Suppressing lipolysis increases inter-
leukin-6 at rest and during prolonged moderate-intensity exercise in humans. J
Appl Physiol 97: 689-696, 2004.
63. Jackson MJ, Edwards RH and Symons MC. Electron spin resonance studies of
intact mammalian skeletal muscle. Biochim Biophys Acta 847: 185-190, 1985.
64. Jensen MD, Caruso M, Heiling V and Miles JM. Insulin regulation of lipolysis in
nondiabetic and IDDM subjects. Diabetes 38: 1595-1601, 1989.
65. Ji LL, Gomez-Cabrera MC, STEINHAFEL N and Vina J. Acute exercise activates
nuclear factor (NF)-{kappa}B signaling pathway in rat skeletal muscle. FASEB J
18: 1499-1506, 2004.
66. Jonsdottir IH, Schjerling P, Ostrowski K, Asp S, Richter EA and Pedersen BK.
Muscle contractions induce interleukin-6 mRNA production in rat skeletal mus-
cles. J Physiol 528: 157-163, 2001.
67. Kado S, Nagase T and Nagata N. Circulating levels of interleukin-6, its soluble
receptor and interleukin-6/interleukin-6 receptor complexes in patients with type
2 diabetes mellitus. Acta Diabetologica 36: 67-72, 1999.
68. Kanemaki T, Kitade H, Kaibori M, Sakitani K, Hiramatsu Y, Kamiyama Y, Ito S
24 • Interleukin-6 in acute exercise and training
and Okumura T. Interleukin 1beta and interleukin 6, but not tumor necrosis factor
alpha, inhibit insulin-stimulated glycogen synthesis in rat hepatocytes. Hepatol-
ogy 27: 1296-1303, 1998.
69. Keller C, Keller P, Marshal S and Pedersen BK. IL-6 gene expression in human
adipose tissue in response to exercise--effect of carbohydrate ingestion. J Physiol
550: 927-931, 2003.
70. Keller C, Steensberg A, Hansen AK, Fischer CP, Plomgaard P and Pedersen BK.
The effect of exercise, training, and glycogen availability on IL-6 receptor
expression in human skeletal muscle. J Appl Physiol 99: 2075-2079, 2005.
71. Keller C, Steensberg A, Pilegaard H, Osada T, Saltin B, Pedersen BK and Neufer
PD. Transcriptional activation of the IL-6 gene in human contracting skeletal
muscle: influence of muscle glycogen content. FASEB J 15: 2748-50, 2001.
72. Keller P, Keller C, Carey AL, Jauffred S, Fischer CP, Steensberg A and Pedersen
BK. Interleukin-6 production by contracting human skeletal muscle: autocrine
regulation by IL-6. Biochem Biophys Res Commun 310: 550-554, 2003.
73. Keller P, Keller C, Robinson LE and Pedersen BK. Epinephrine infusion increas-
es adipose interleukin-6 gene expression and systemic levels in humans. J Appl
Physiol 97: 1309-1312, 2004.
74. Kestler DP, Agarwal S, Cobb J, Goldstein KM and Hall RE. Detection and analy-
sis of an alternatively spliced isoform of interleukin-6 mRNA in peripheral blood
mononuclear cells. Blood 86: 4559-4567, 1995.
75. Kim HJ, Higashimori T, Park SY, Choi H, Dong J, Kim YJ, Noh HL, Cho YR,
Cline G, Kim YB and Kim JK. Differential Effects of Interleukin-6 and -10 on
Skeletal Muscle and Liver Insulin Action In Vivo. Diabetes 53: 1060-1067, 2004.
76. Kishimoto T, Akira S, Narazaki M and Taga T. Interleukin-6 family of cytokines
and gp130. Blood 86: 1243-1254, 1995.
77. Klover PJ, Clementi AH and Mooney RA. Interleukin-6 depletion selectively
improves hepatic insulin action in obesity. Endocrinology 146: 3417-27, 2005.
78. Klover PJ, Zimmers TA, Koniaris LG and Mooney RA. Chronic Exposure to
Interleukin-6 Causes Hepatic Insulin Resistance in Mice. Diabetes 52: 2784-
2789, 2003.
79. Kohut ML, McCann DA, Russell DW, Konopka DN, Cunnick JE, Franke WD,
Castillo MC, Reighard AE and Vanderah E. Aerobic exercise, but not
flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent
of [beta]-blockers, BMI, and psychosocial factors in older adults. Brain, Behav-
ior, and Immunity 20: 201-209, 2006.
80. Kopp E and Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin.
Science 265: 956-959, 1994.
81. Kosmidou I, Vassilakopoulos T, Xagorari A, Zakynthinos S, Papapetropoulos A
and Roussos C. Production of interleukin-6 by skeletal myotubes: role of reactive
oxygen species. Am J Respir Cell Mol Biol 26: 587-593, 2002.
82. Krogh-Madsen R, Plomgaard P, Moller K, Mittendorfer B and Pedersen BK.
Influence of TNF-{alpha} and IL-6 infusions on insulin sensitivity and expres-
sion of IL-18 in humans. Am J Physiol Endocrinol Metab 291: E108-E114, 2006.
83. Kubis HP, Hanke N, Scheibe RJ, Meissner JD and Gros G. Ca2+ transients acti-
vate calcineurin/NFATc1 and initiate fast-to-slow transformation in a primary
skeletal muscle culture. Am J Physiol Cell Physiol 285: C56-C63, 2003.
84. Langberg H, Olesen JL, Gemmer C and Kjaer M. Substantial elevation of inter-
Interleukin-6 in acute exercise and training • 25
leukin-6 concentration in peritendinous tissue, in contrast to muscle, following
prolonged exercise in humans. J Physiol 542: 985-990, 2002.
85. Larsen AI, Aukrust P, Aarsland T and Dickstein K. Effect of aerobic exercise
training on plasma levels of tumor necrosis factor alpha in patients with heart
failure. The American Journal of Cardiology 88: 805-808, 2001.
86. Li TL and Gleeson M. The effects of carbohydrate supplementation during the
second of two prolonged cycling bouts on immunoendocrine responses. Eur J
Appl Physiol 95: 391-399, 2005.
87. Lundby C and Steensberg A. Interleukin-6 response to exercise during acute and
chronic hypoxia. European Journal of Applied Physiology 91: 88-93, 2004.
88. Lyngso D, Simonsen L and Bulow J. Interleukin-6 production in human subcuta-
neous abdominal adipose tissue: the effect of exercise. J Physiol 543: 373-378,
89. MacDonald C, Wojtaszewski JFP, Pedersen BK, Kiens B and Richter EA. Inter-
leukin-6 release from human skeletal muscle during exercise: relation to AMPK
activity. J Appl Physiol 95: 2273-2277, 2003.
90. MacIntyre DL, Sorichter S, Mair J, Berg A and McKenzie DC. Markers of
inflammation and myofibrillar proteins following eccentric exercise in humans.
Eur J Appl Physiol 84: 180-186, 2001.
91. Mandell GL, Rubin W and Hook EW. The effect of an NADH oxidase inhibitor
(hydrocortisone) on polymorphonuclear leukocyte bactericidal activity. J Clin
Invest 49: 1381-1388, 1970.
92. Margeli A, Skenderi K, Tsironi M, Hantzi E, Matalas AL, Vrettou C, Kanavakis
E, Chrousos G and Papassotiriou I. Dramatic elevations of interleukin-6 and
acute phase reactants in athletes participating in the ultradistance foot race “spar-
tathlon”: severe systemic inflammation and lipid and lipoprotein changes in pro-
tracted exercise. J Clin Endocrinol Metab 90: 3914-8, 2005.
93. Matsusaka T, Fujikawa K, Nishio Y, Mukaida N, Matsushima K, Kishimoto T and
Akira S. Transcription factors NF-IL6 and NF-kappa B synergistically activate
transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc
Natl Acad Sci U S A 90: 10193-10197, 1993.
94. Matthys P, Mitera T, Heremans H, Van Damme J and Billiau A. Anti-gamma
interferon and anti-interleukin-6 antibodies affect staphylococcal enterotoxin B-
induced weight loss, hypoglycemia, and cytokine release in D-galactosamine-
sensitized and unsensitized mice. Infect Immun 63: 1158-1164, 1995.
95. May LT, Santhanam U, Tatter SB, Bhardwaj N, Ghrayeb J and Sehgal PB. Phos-
phorylation of secreted forms of human beta 2-interferon/hepatocyte stimulating
factor/interleukin-6. Biochem Biophys Res Commun 152: 1144-1150, 1988.
96. Mazzeo RS, Donovan D, Fleshner M, Butterfield GE, Zamudio S, Wolfel EE and
Moore LG. Interleukin-6 response to exercise and high-altitude exposure: influ-
ence of alpha -adrenergic blockade. J Appl Physiol 91: 2143-2149, 2001.
97. McGee SL and Hargreaves M. Exercise and Myocyte Enhancer Factor 2 Regula-
tion in Human Skeletal Muscle. Diabetes 53: 1208-1214, 2004.
98. Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S
and Coppack SW. Subcutaneous Adipose Tissue Releases Interleukin-6, But Not
Tumor Necrosis Factor-{alpha}, in Vivo. J Clin Endocrinol Metab 82: 4196-4200,
99. Montero-Julian FA, Klein B, Gautherot E and Brailly H. Pharmacokinetic study
26 • Interleukin-6 in acute exercise and training
of anti-interleukin-6 (IL-6) therapy with monoclonal antibodies: enhancement of
IL-6 clearance by cocktails of anti-IL-6 antibodies. Blood 85: 917-924, 1995.
100. Moore KW, Garra A, Malefyt RW, Vieira P and Mosmann TR. Interleukin-10.
Annual Review of Immunology 11: 165-190, 1993.
101. Naitoh Y, Fukata J, Tominaga T, Nakai Y, Tamai S, Mori K and Imura H. Inter-
leukin-6 stimulates the secretion of adrenocorticotropic hormone in conscious,
freely-moving rats. Biochem Biophys Res Commun 155: 1459-1463, 1988.
102. Nehlsen-Cannarella SL, Fagoaga OR, Nieman DC, Henson DA, Butterworth DE,
Schmitt RL, Bailey EM, Warren BJ, Utter A and Davis JM. Carbohydrate and the
cytokine response to 2.5 h of running. J Appl Physiol 82: 1662-1667, 1997.
103. Nemet D, Eliakim A, Zaldivar F and Cooper DM. The Effect of rhIL-6 Infusion
on GH-->IGF-I Axis Mediators in Humans. Am J Physiol Regul Integr Comp
Physiol 291: R1663-8, 2006.
104. Nicklas BJ, Ambrosius W, Messier SP, Miller GD, Penninx BW, Loeser RF, Palla
S, Bleecker E and Pahor M. Diet-induced weight loss, exercise, and chronic
inflammation in older, obese adults: a randomized controlled clinical trial. Am J
Clin Nutr 79: 544-551, 2004.
105. Nielsen HB, Secher NH, Christensen NJ and Pedersen BK. Lymphocytes and NK
cell activity during repeated bouts of maximal exercise. Am J Physiol 271: R222-
R227, 1996.
106. Nieman DC, Davis JM, Henson DA, Gross SJ, Dumke CL, Utter AC, Vinci DM,
Carson JA, Brown A, McAnulty SR, McAnulty LS and Triplett NT. Muscle
cytokine mRNA changes after 2.5 h of cycling: influence of carbohydrate. Med
Sci Sports Exerc 37: 1283-1290, 2005.
107. Nieman DC, Davis JM, Henson DA, Walberg-Rankin J, Shute M, Dumke CL,
Utter AC, Vinci DM, Carson JA, Brown A, Lee WJ, McAnulty SR and McAnulty
LS. Carbohydrate ingestion influences skeletal muscle cytokine mRNA and plas-
ma cytokine levels after a 3-h run. J Appl Physiol 94: 1917-1925, 2003.
108. Nieman DC, Henson DA, McAnulty SR, McAnulty L, Swick NS, Utter AC, Vinci
DM, Opiela SJ and Morrow JD. Influence of vitamin C supplementation on
oxidative and immune changes after an ultramarathon. J Appl Physiol 92: 1970-
1977, 2002.
109. Nieman DC, Nehlsen-Cannarella SL, Fagoaga OR, Henson DA, Utter A, Davis
JM, Williams F and Butterworth DE. Influence of mode and carbohydrate on the
cytokine response to heavy exertion. Med Sci Sports Exerc 30: 671-678, 1998.
110. Nieman DC, Peters EM, Henson DA, Nevines EI and Thompson MM. Influence
of vitamin C supplementation on cytokine changes following an ultramarathon. J
Interferon Cytokine Res 20: 1029-1035, 2000.
111. Nieman DC, Dumke CL, Henson DA, McAnulty SR, Gross SJ and Lind RH.
Muscle damage is linked to cytokine changes following a 160-km race. Brain,
Behavior, and Immunity 19: 398-403, 2005.
112. Nieman DC, Henson DA, Smith LL, Utter AC, Vinci DM, Davis JM, Kaminsky
DE and Shute M. Cytokine changes after a marathon race. J Appl Physiol 91:
109-114, 2001.
113. Niess AM, Fehrenbach E, Lehmann R, Opavsky L, Jesse M, Northoff H and
Dickhuth HH. Impact of elevated ambient temperatures on the acute immune
response to intensive endurance exercise. European Journal of Applied Physiolo-
gy 89: 344-351, 2003.
Interleukin-6 in acute exercise and training • 27
114. Niess AM, Fehrenbach E, Strobel G, Roecker K, Schneider EM, Buergler J, Fuss
S, Lehmann R, Northoff H and Dickhuth HH. Evaluation of Stress Responses to
Interval Training at Low and Moderate Altitudes. Medicine & Science in Sports
& Exercise February 35: 263-269, 2003.
115. Northoff H and Berg A. Immunologic mediators as parameters of the reaction to
strenuous exercise. Int J Sports Med 12 Suppl 1: S9-15, 1991.
116. Nosaka K and Clarkson PM. Changes in indicators of inflammation after eccen-
tric exercise of the elbow flexors. Med Sci Sports Exerc 28: 953-961, 1996.
117. Nybo L, Moller K, Pedersen BK, Nielsen B and Secher NH. Association between
fatigue and failure to preserve cerebral energy turnover during prolonged exer-
cise. Acta Physiologica Scandinavica 179: 67-74, 2003.
118. Nybo L, Nielsen B, Pedersen BK, Moller K and Secher NH. Interleukin-6 release
from the human brain during prolonged exercise. J Physiol 542: 991-995, 2002.
119. Ostrowski K, Hermann C, Bangash A, Schjerling P, Nielsen JN and Pedersen BK.
A trauma-like elevation of plasma cytokines in humans in response to treadmill
running. J Physiol 513 ( Pt 3): 889-894, 1998.
120. Ostrowski K, Rohde T, Asp S, Schjerling P and Pedersen BK. Pro- and anti-
inflammatory cytokine balance in strenuous exercise in humans. J Physiol 515 (
Pt 1): 287-291, 1999.
121. Ostrowski K, Rohde T, Zacho M, Asp S and Pedersen BK. Evidence that inter-
leukin-6 is produced in human skeletal muscle during prolonged running. J Phys-
iol 508 ( Pt 3): 949-953, 1998.
122. Ostrowski K, Schjerling P and Pedersen BK. Physical activity and plasma interleukin-6
in humans--effect of intensity of exercise. Eur J Appl Physiol 83: 512-515, 2000.
123. Panagiotakos DB, Pitsavos C, Chrysohoou C, Kavouras S and Stefanadis C. The
associations between leisure-time physical activity and inflammatory and coagu-
lation markers related to cardiovascular disease: the ATTICA Study. Preventive
Medicine 40: 432-437, 2005.
124. Papanicolaou DA, Petrides JS, Tsigos C, Bina S, Kalogeras KT, Wilder R, Gold
PW, Deuster PA and Chrousos GP. Exercise stimulates interleukin-6 secretion:
inhibition by glucocorticoids and correlation with catecholamines. Am J Physiol
Endocrinol Metab 271: E601-E605, 1996.
125. Paroo Z and Noble EG. Isoproterenol potentiates exercise-induction of Hsp70 in
cardiac and skeletal muscle. Cell Stress Chaperones 4: 199-204, 1999.
126. Pedersen BK and Hoffmann-Goetz L. Exercise and the immune system: Regula-
tion, integration and adaption. Physiol Rev 80: 1055-1081, 2000.
127. Pedersen M, Steensberg A, Keller C, Osada T, Zacho M, Saltin B, Febbraio MA
and Pedersen BK. Does the aging skeletal muscle maintain its endocrine func-
tion? Exerc Immunol Rev 10: 42-55, 2004.
128. Penkowa M, Keller C, Keller P, Jauffred S and Pedersen BK. Immunohistochemi-
cal detection of interleukin-6 in human skeletal muscle fibers following exercise.
FASEB J 17: 2166-2168, 2003.
129. Pepys MB, Hawkins PN, Kahan MC, Tennent GA, Gallimore JR, Graham D,
Sabin CA, Zychlinsky A and de Diego J. Proinflammatory Effects of Bacterial
Recombinant Human C-Reactive Protein Are Caused by Contamination With
Bacterial Products, Not by C-Reactive Protein Itself. Circ Res 97: e97-103, 2005.
130. Pepys MB and Hirschfield GM. C-reactive protein: a critical update. J Clin Invest
111: 1805-1812, 2003.
28 • Interleukin-6 in acute exercise and training
131. Perlstein RS, Whitnall MH, Abrams JS, Mougey EH and Neta R. Synergistic
roles of interleukin-6, interleukin-1, and tumor necrosis factor in the adrenocorti-
cotropin response to bacterial lipopolysaccharide in vivo. Endocrinology 132:
946-952, 1993.
132. Peters EM, Anderson R and Theron AJ. Attenuation of increase in circulating cor-
tisol and enhancement of the acute phase protein response in vitamin C-supple-
mented ultramarathoners. Int J Sports Med 22: 120-126, 2001.
133. Petersen EW, Carey AL, Sacchetti M, Steinberg GR, Macaulay SL, Febbraio MA
and Pedersen BK. Acute IL-6 treatment increases fatty acid turnover in elderly
humans in vivo and in tissue culture in vitro. Am J Physiol Endocrinol Metab
288: E155-E162, 2005.
134. Petersen EW, Ostrowski K, Ibfelt T, Richelle M, Offord E, Halkjaer-Kristensen J
and Pedersen BK. Effect of vitamin supplementation on cytokine response and on
muscle damage after strenuous exercise. Am J Physiol Cell Physiol 280: C1570-
C1575, 2001.
135. Phillips SM, Green HJ, Tarnopolsky MA, Heigenhauser GJ, Hill RE and Grant
SM. Effects of training duration on substrate turnover and oxidation during exer-
cise. J Appl Physiol 81: 2182-2191, 1996.
136. Pilegaard H, Saltin B and Neufer PD. Exercise induces transient transcriptional
activation of the PGC-1alpha gene in human skeletal muscle. J Physiol 546: 851-
858, 2003.
137. Plomgaard P, Penkowa M and Pedersen BK. Fiber type specific expression of
TNF-alpha, IL-6 and IL-18 in human skeletal muscles. Exerc Immunol Rev 11:
53-63, 2005.
138. Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR and Ped-
ersen BK. Tumor Necrosis Factor-{alpha} Induces Skeletal Muscle Insulin Resis-
tance in Healthy Human Subjects via Inhibition of Akt Substrate 160 Phosphory-
lation. Diabetes 54: 2939-2945, 2005.
139. Poupart P, Vandenabeele P, Cayphas S, Van Snick J, Haegeman G, Kruys V, Fiers
W and Content J. B cell growth modulating and differentiating activity of recom-
binant human 26-kd protein (BSF-2, HuIFN-beta 2, HPGF). EMBO J 6: 1219-
1224, 1987.
140. Pretolani M. Interleukin-10: an anti-inflammatory cytokine with therapeutic
potential. Clinical & Experimental Allergy 29: 1164-1171, 1999.
141. Pritts TA, Hungness ES, Hershko DD, Robb BW, Sun X, Luo GJ, Fischer JE,
Wong HR and Hasselgren PO. Proteasome inhibitors induce heat shock response
and increase IL-6 expression in human intestinal epithelial cells. Am J Physiol
Regul Integr Comp Physiol 282: R1016-R1026, 2002.
142. Pue CA, Mortensen RF, Marsh CB, Pope HA and Wewers MD. Acute phase lev-
els of C-reactive protein enhance IL-1 beta and IL-1ra production by human
blood monocytes but inhibit IL-1 beta and IL-1ra production by alveolar
macrophages. J Immunol 156: 1594-1600, 1996.
143. Rhind SG, Gannon GA, Shephard RJ and Shek PN. Indomethacin modulates cir-
culating cytokine responses to strenuous exercise in humans. Cytokine 19: 153-
158, 2002.
144. Rohde T, MacLean DA, Richter EA, Kiens B and Pedersen BK. Prolonged sub-
maximal eccentric exercise is associated with increased levels of plasma IL-6.
Am J Physiol 273: E85-E91, 1997.
Interleukin-6 in acute exercise and training • 29
145. Ronsen O, Holm K, Staff H, Opstad PK, Pedersen BK and Bahr R. No effect of
seasonal variation in training load on immuno-endocrine responses to acute
exhaustive exercise. Scandinavian Journal of Medicine and Science in Sports 11:
141-148, 2001.
146. Ronsen O, Lea T, Bahr R and Pedersen BK. Enhanced plasma IL-6 and IL-1ra
responses to repeated vs. single bouts of prolonged cycling in elite athletes. J
Appl Physiol 92: 2547-2553, 2002.
147. Rosendal L, Sogaard K, Kjaer M, Sjogaard G, Langberg H and Kristiansen J.
Increase in interstitial interleukin-6 of human skeletal muscle with repetitive low-
force exercise. J Appl Physiol 98: 477-481, 2005.
148. Rotter V, Nagaev I and Smith U. Interleukin-6 (IL-6) Induces Insulin Resistance
in 3T3-L1 Adipocytes and Is, Like IL-8 and Tumor Necrosis Factor-{alpha},
Overexpressed in Human Fat Cells from Insulin-resistant Subjects. J Biol Chem
278: 45777-45784, 2003.
149. Rowsey PJ and Kluger MJ. Corticotropin releasing hormone is involved in exer-
cise-induced elevation in core temperature. Psychoneuroendocrinology 19: 179-
187, 1994.
150. Saltin B and Rowell LB. Functional adaptations to physical activity and inactivi-
ty. Fed Proc 39: 1506-1513, 1980.
151. Samra JS, Clark ML, Humphreys SM, Macdonald IA, Matthews DR and Frayn
KN. Effects of morning rise in cortisol concentration on regulation of lipolysis in
subcutaneous adipose tissue. Am J Physiol Endocrinol Metab 271: E996-1002,
152. Schantz P, Henriksson J and Jansson E. Adaptation of human skeletal muscle to
endurance training of long duration. Clin Physiol 3: 141-151, 1983.
153. Schindler R, Mancilla J, Endres S, Ghorbani R, Clark SC and Dinarello CA. Cor-
relations and interactions in the production of interleukin-6 (IL- 6), IL-1, and
tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses
IL-1 and TNF. Blood 75: 40-47, 1990.
154. Schreck R, Rieber P and Baeuerle PA. Reactive oxygen intermediates as appar-
ently widely used messengers in the activation of the NF-kappa B transcription
factor and HIV-1. The EMBO Journal 10: 2247-2258, 1991.
155. Sehgal PB, Zilberstein A, Ruggieri RM, May LT, Ferguson-Smith A, Slate DL,
Revel M and Ruddle FH. Human Chromosome 7 Carries the {beta} 2 Interferon
Gene. PNAS 83: 5219-5222, 1986.
156. Senn JJ, Klover PJ, Nowak IA and Mooney RA. Interleukin-6 Induces Cellular
Insulin Resistance in Hepatocytes. Diabetes 51: 3391-3399, 2002.
157. Senn JJ, Klover PJ, Nowak IA, Zimmers TA, Koniaris LG, Furlanetto RW and
Mooney RA. Suppressor of Cytokine Signaling-3 (SOCS-3), a Potential Mediator
of Interleukin-6-dependent Insulin Resistance in Hepatocytes. J Biol Chem 278:
13740-13746, 2003.
158. Shi H, Tzameli I, Bjorbaek C and Flier JS. Suppressor of Cytokine Signaling 3 Is
a Physiological Regulator of Adipocyte Insulin Signaling. J Biol Chem 279:
34733-34740, 2004.
159. Singh A, Papanicolaou DA, Lawrence LL, Howell EA, Chrousos GP and Deuster
PA. Neuroendocrine responses to running in women after zinc and vitamin E sup-
plementation. Med Sci Sports Exerc 31: 536-542, 1999.
160. Sopasakis VR, Sandqvist M, Gustafson B, Hammarstedt A, Schmelz M, Yang X,
30 • Interleukin-6 in acute exercise and training
Jansson PA and Smith U. High Local Concentrations and Effects on Differentia-
tion Implicate Interleukin-6 as a Paracrine Regulator. Obesity Res 12: 454-460,
161. Starkie R, Ostrowski SR, Jauffred S, Febbraio M and Pedersen BK. Exercise and
IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans.
FASEB J 17: 884-886, 2003.
162. Starkie RL, Angus DJ, Rolland J, Hargreaves M and Febbraio MA. Effect of pro-
longed, submaximal exercise and carbohydrate ingestion on monocyte intracellu-
lar cytokine production in humans. J Physiol 528: 647-655, 2000.
163. Starkie RL, Arkinstall MJ, Koukoulas I, Hawley JA and Febbraio MA. Carbohy-
drate ingestion attenuates the increase in plasma interleukin-6, but not skeletal
muscle interleukin-6 mRNA, during exercise in humans. J Physiol 533: 585-591,
164. Starkie RL, Hargreaves M, Rolland J and Febbraio MA. Heat stress, cytokines,
and the immune response to exercise. Brain, Behavior, and Immunity 19: 404-
412, 2005.
165. Steensberg A, Febbraio MA, Osada T, Schjerling P, Van Hall G, Saltin B and Ped-
ersen BK. Interleukin-6 production in contracting human skeletal muscle is influ-
enced by pre-exercise muscle glycogen content. J Physiol 537: 633-639, 2001.
166. Steensberg A, Fischer CP, Keller C, Moller K and Pedersen BK. IL-6 enhances
plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Endocrinol Metab
285: E433-E437, 2003.
167. Steensberg A, Fischer CP, Sacchetti M, Keller C, Osada T, Schjerling P, Van Hall
G, Febbraio MA and Pedersen BK. Acute interleukin-6 administration does not
impair muscle glucose uptake or whole-body glucose disposal in healthy humans.
J Physiol 548: 631-8, 2003.
168. Steensberg A, Keller C, Starkie RL, Osada T, Febbraio MA and Pedersen BK. IL-
6 and TNF-alpha expression in, and release from, contracting human skeletal
muscle. Am J Physiol Endocrinol Metab 283: E1272-E1278, 2002.
169. Steensberg A, Toft AD, Bruunsgaard H, Sandmand M, Halkjaer-Kristensen J and
Pedersen BK. Strenuous exercise decreases the percentage of type 1 T cells in the
circulation. J Appl Physiol 91: 1708-1712, 2001.
170. Steensberg A, Toft AD, Schjerling P, Halkjaer-Kristensen J and Pedersen BK.
Plasma interleukin-6 during strenuous exercise: role of epinephrine. Am J Physiol
Cell Physiol 281: 1001-1004, 2001.
171. Steensberg A, Van Hall G, Keller C, Osada T, Schjerling P, Pedersen BK, Saltin B
and Febbraio MA. Muscle glycogen content and glucose uptake during exercise
in humans: influence of prior exercise and dietary manipulation. J Physiol 541:
273-281, 2002.
172. Steensberg A, Van Hall G, Osada T, Sacchetti M, Saltin B and Klarlund PB. Pro-
duction of interleukin-6 in contracting human skeletal muscles can account for
the exercise-induced increase in plasma interleukin-6. J Physiol 529 Pt 1: 237-
242, 2000.
173. Stith RD and Luo J. Endocrine and carbohydrate responses to interleukin-6 in
vivo. Circ Shock 44: 210-215, 1994.
174. Stouthard JM, Romijn JA, van der PT, Endert E, Klein S, Bakker PJ, Veenhof CH
and Sauerwein HP. Endocrinologic and metabolic effects of interleukin-6 in
humans. Am J Physiol 268: E813-E819, 1995.
Interleukin-6 in acute exercise and training • 31
175. Suzuki K, Nakaji S, Yamada M, Liu Q, Kurakake S, Okamura N, Kumae T,
Umeda T and Sugawara K. Impact of a Competitive Marathon Race on Systemic
Cytokine and Neutrophil Responses. Med Sci Sports Exerc 35: 348-355, 2003.
176. Suzuki K, Yamada M, Kurakake S, Okamura N, Yamaya K, Liu Q, Kudoh S,
Kowatari K, Nakaji S and Sugawara K. Circulating cytokines and hormones with
immunosuppressive but neutrophil-priming potentials rise after endurance exer-
cise in humans. Eur J Appl Physiol 81: 281-287, 2000.
177. Suzuki K, Totsuka M, Nakaji S, Yamada M, Kudoh S, Liu Q, Sugawara K,
Yamaya K and Sato K. Endurance exercise causes interaction among stress hor-
mones, cytokines, neutrophil dynamics, and muscle damage. J Appl Physiol 87:
1360-1367, 1999.
178. Thompson D, Williams C, Garcia-Roves P, McGregor SJ, McArdle F and Jackson
MJ. Post-exercise vitamin C supplementation and recovery from demanding exer-
cise. Eur J Appl Physiol 89: 393-400, 2003.
179. Thompson D, Williams C, McGregor SJ, Nicholas CW, McArdle F, Jackson MJ
and Powell JR. Prolonged vitamin C supplementation and recovery from demand-
ing exercise. Int J Sport Nutr Exerc Metab 11: 466-481, 2001.
180. Tilg H, Trehu E, Atkins MB, Dinarello CA and Mier JW. Interleukin-6 (IL-6) as
an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist
and soluble tumor necrosis factor receptor p55. Blood 83: 113-118, 1994.
181. Timmons BW, Hamadeh MJ, Devries MC and Tarnopolsky MA. Influence of
gender, menstrual phase, and oral contraceptive use on immunological changes in
response to prolonged cycling. J Appl Physiol 99: 979-985, 2005.
182. Toft AD, Bruunsgaard H, Ibfelt T, Halkjaer-Kristensen J and Pedersen BK. The
cytokine response to eccentric exercise in young versus elderly humans. J Physiol
283: C289-C295, 2002.
183. Toft AD, Thorn M, Ostrowski K, Asp S, Moller K, Iversen S, Hermann C, Son-
dergaard SR and Pedersen BK. N-3 polyunsaturated fatty acids do not affect
cytokine response to strenuous exercise. J Appl Physiol 89: 2401-2406, 2000.
184. Tsigos C, Papanicolaou DA, Defensor R, Mitsiadis CS, Kyrou I and Chrousos
GP. Dose effects of recombinant human interleukin-6 on pituitary hormone secre-
tion and energy expenditure. Neuroendocrinology 66: 54-62, 1997.
185. Tsigos C, Papanicolaou DA, Kyrou I, Defensor R, Mitsiadis CS and Chrousos
GP. Dose-dependent effects of recombinant human interleukin-6 on glucose regu-
lation. J Clin Endocrinol Metab 82: 4167-4170, 1997.
186. Ullum H, Haahr PM, Diamant M, Palmo J, Halkjaer-Kristensen J and Pedersen
BK. Bicycle exercise enhances plasma IL-6 but does not change IL-1 alpha, IL-1
beta, IL-6, or TNF-alpha pre-mRNA in BMNC. J Appl Physiol 77: 93-97, 1994.
187. Van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, His-
cock N, Moller K, Saltin B, Febbraio MA and Pedersen BK. Interleukin-6 stimu-
lates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 88: 3005-
3010, 2003.
188. van Helvoort HAC, Heijdra YF, Heunks LMA, Meijer PLM, Ruitenbeek W, Thijs
HMH and Dekhuijzen PNR. Supplemental Oxygen Prevents Exercise-induced
Oxidative Stress in Muscle-wasted Patients with Chronic Obstructive Pulmonary
Disease. Am J Respir Crit Care Med 173: 1122-1129, 2006.
189. Vassilakopoulos T, Karatza MH, Katsaounou P, Kollintza A, Zakynthinos S and
Roussos C. Antioxidants attenuate the plasma cytokine response to exercise in
32 • Interleukin-6 in acute exercise and training
humans. J Appl Physiol 94: 1025-1032, 2003.
190. Wallen ES, Buettner GR and Moseley PL. Oxidants differentially regulate the
heat shock response. Int J Hyperthermia 13: 517-524, 1997.
191. Wang P, Wu P, Siegel MI, Egan RW and Billah MM. IL-10 inhibits transcription
of cytokine genes in human peripheral blood mononuclear cells. J Immunol 153:
811-816, 1994.
192. Watt MJ, Carey AL, Wolsk-Petersen E, Kraemer FB, Pedersen BK and Febbraio
MA. Hormone-sensitive lipase is reduced in the adipose tissue of patients with
type 2 diabetes mellitus: influence of IL-6 infusion. Diabetologia 48: 105-112,
193. Welch WJ, Garrels JI, Thomas GP, Lin JJ and Feramisco JR. Biochemical charac-
terization of the mammalian stress proteins and identification of two stress pro-
teins as glucose- and Ca2+-ionophore- regulated proteins. J Biol Chem 258:
7102-7111, 1983.
194. Willoughby DS, McFarlin B and Bois C. Interleukin-6 Expression After Repeated
Bouts of Eccentric Exercise. International Journal of Sports Medicine 15-21,
195. Yamada M, Suzuki K, Kudo S, Totsuka M, Nakaji S and Sugawara K. Raised
plasma G-CSF and IL-6 after exercise may play a role in neutrophil mobilization
into the circulation. J Appl Physiol 92: 1789-1794, 2002.
196. Zhang D, Sun M, Samols D and Kushner I. STAT3 Participates in Transcriptional
Activation of the C-reactive Protein Gene by Interleukin-6. J Biol Chem 271:
9503-9509, 1996.
Interleukin-6 in acute exercise and training • 33
... Nonetheless, the clinical importance is that HIIT or MICT produced short-term transitory immunologic stress in older adults. Together, we revisited the importance of IL-6 and IL-10, as previously shown [26,27]. ...
... Here stood evident that both exercise regimes induced stress on the immune system, already demonstrated by different authors [26,27], including, as shown previously for our group or HIIT [28]. Even more recently, a Th-17 immune response profile, also pro-inflammatory, may be necessary for the long-term effects achieved by people who completed HIIT [29][30][31]. ...
... The data presented here show that physical exercises modify the leukogram cell count and the cytokine kinetics of the Th1, Th2, and Th17 profile, including correlations between the cytokine results. The importance of IL-6 and IL-10 has already been revisited [26,27]. This stress on the immune system, already demonstrated by different authors [26,27], was also demonstrated in our study. ...
Full-text available
Here we investigated the acute effects of an exhaustive intermittent exercise session on immunological parameters of the elderly and the subsequent incidence of upper respiratory tract infections and compare with the moderate-intensity. To do so, ixty-three old subjects were divided into three groups HIIT (n=21) submitted at one High-intensity interval training, SCG (n=21) kept in a sedentary state, and MICT (n=21) submitted at moderate intensity walking. Blood were collected at 5 time points, before, immediately after, 2h, 24h, and 48h after the intervention. In result the IL-6 and TNF-α were overexpressed immediately after the IL-10 stood overexpressed and correlated with IL-17, denoting an inflammatory process, and evidencing an immunologic competence without enhancement of the prevalence of upper respiratory infection tract (URTIs). So a modulation in the balance of Th1/Th2/Th17 cytokines and leukocytes, these modifications did not cause the effect characterized as an immunological window. Perhaps, the typical inflammation process, with IL-10 and IL-17 participation could also produce benefits to combat infections, a pertinent discussion during a post-pandemic time; we consider it a safe exercise program for older adults.
... ISSN-L 1993 Exercise performed acutely has a positive effect on inhibiting the development of chronic disease through the post-exercise inflammatory response (Kramer & Goodyear, 2007). One of the inflammatory responses that increase post-exercise is muscle interleukin-6 (IL-6) levels (Fischer, 2006;Pedersen & Febbraio, 2008). Muscle IL-6 levels increase up to 100-fold during exercise and decrease rapidly after exercise (Docherty et al., 2022). ...
... However, several studies reported inconsistent results (increase, decrease or no significant change) in IL-6 levels following moderate-intensity exercise (Mendham et al., 2011;Dimitrov et al., 2017;Windsor et al., 2018;Andarianto et al., 2022;Sugiharto et al., 2022). Factors that might influence the inconsistency of results at the IL-6 level, namely differences in exercise mode, exercise intensity, and duration of exercise (Fischer et al., 2006;Nindl et al., 2009;Mendham et al., 2011;Hennigar et al., 2017;Cerqueira et al., 2020;Andarianto et al., 2022). Therefore, the aim of this study was to prove the effect of acute moderate-intensity endurance and strength exercise on increasing IL-6 levels in obese females. ...
... IL-6 has a dual role namely, it can act as a proinflammatory cytokine, and act as an anti-inflammatory when released by contracting muscles (Zunner et al., 2022;Pedersen & Febbraio, 2008). IL-6 has regenerative and anti-inflammatory functions, especially when secreted by skeletal muscle during exercise (Kistner et al., 2022;Fischer 2006). As an anti-inflammatory cytokine, IL-6 has been reported to inhibit pro-inflammatory effects, like inhibiting TNF-α, increasing M2 macrophage polarization, and insulin sensitivity (Sindhu et al. 2015;Pedersen et al., 2001;Mauer et al., 2014). ...
Full-text available
The study purpose was to prove the effect of acute moderate-intensity endurance and strength exercise on increasing IL-6 levels in obese females. Materials and methods. A total of 21 obese women aged 20-25 years were recruited from among university students and given two modes of acute exercise intervention, namely moderate-intensity endurance and strength exercise carried out for 35 minutes/session. Subjects were divided randomly into three groups, namely K1 (control group without intervention; n = 7), K2 (Acute moderate-intensity endurance exercise; n = 7), K3 (Acute moderate-intensity strength exercise; n = 7). ELISA was used to analyze serum IL-6 levels before and after exercise. The data analysis technique used the One-way ANOVA test and continued with the Tukey HSD post-hoc test with a significance level of 5%. Results. The results of the One-way ANOVA test showed that there was a significant difference between serum IL-6 levels after exercise and delta (Δ) in the three groups (p ≤ 0.01). The results of the Tukey HSD post-hoc test showed that there was a significant difference between serum IL-6 levels after exercise and delta (Δ) at K3 with K1 (p ≤ 0.01), K3with K2 (p ≤ 0.01), while there was no significant difference in serum IL-6 levels (p ≥ 0.05) at K2 with K1. Conclusions. Overall, our study concluded that 35 min/session of acute moderate-intensity strength exercise was effective in increasing anti-inflammatory cytokines, such as IL-6, in obese females.
... It has been suggested that, among other things, it is possible to mention the increase in the production of free radicals and the activation of the NF-KB signaling pathway and the increase in heat shock proteins (HSPs) during HIIT training. 24,25 Furthermore, Sarkar et al. (2021) showed that temporary hypoxia caused by HIIT training is a strong stimulus to increase interleukin-6 levels. 26 Fesicher et al. (2005) also revealed that the duration, intensity and recovery time are the determining factors in the acute phase response (APR) to the kinetics of IL-6. ...
... More than 50% of the changes in IL-6 are related to the duration of exercise, and recovery time can also affect the inflammatory response. 24 Brown et al. (2018) suggested that even 48 h after exercise training, IL6 levels are higher than resting levels. Also, these researchers state that increasing IL-6 levels after exercise training causes muscle pain, reduced glycogen availability, and changes in calcium homeostasis caused by activation of mitogen-activated protein kinase (MAPK) and increased stress hormones. ...
... Also, these researchers state that increasing IL-6 levels after exercise training causes muscle pain, reduced glycogen availability, and changes in calcium homeostasis caused by activation of mitogen-activated protein kinase (MAPK) and increased stress hormones. 24,26,27 Previous studies have shown that HIIT produces a small inflammatory cytokine response; However, long-term continuous aerobic exercise produces a much larger inflammatory cytokine response than short-term. 22,25,28,29 Abbreviations: h, Hour; IL-6, Interleukin-6; hs-CRP, High-sensitivity C -reactive protein; CPK, Creatine phosphokinase; LDH, Lactate dehydrogenase; ALT, Alanine transaminase; AST,Aspartate aminotransferase. ...
Full-text available
Introduction: Recently, the use of various high-intensity intermittent training (HIIT) that have quick recovery periods are of great importance. Therefore, the purpose of this research was to investigate the acute effect of HIIT training on the serum levels of inflammatory and muscle damage indices in overweight middle-aged men, as well as the kinetics of these markers at 1, 24, and 48 h after HIIT training. Methods: Twenty-two middle-aged men (40–60 years, BMI 25–30 kg/m2) were divided into two training (n=12) and control (n=10) groups. The HIIT training program consisted of running on treadmill for 30 s with an intensity of 100% maximum aerobic speed (MAV), 30 s active recovery with 50% aerobic speed (4 sets, 4 repetitions and 5 min of rest between each round). Cortisol, IL-6, CRP, ALT, AST, CPK and LDH were evaluated in pre-test, one- hour, 24 and 48 h after HIIT training. Results: Except for the CRP variable, Cortisol, IL-6, CPK, LDH, ALT and AST had a significant increase in one- hour after HIIT compared to the pre-test (P
... In response to acute exercise, plasma IL-6 levels increase nonlinearly over time, peaking at the end of exercise and then falling to the pre-exercise level (27). By contrast, there is a negative association between basal plasma IL-6 levels and amount of regular physical activity, low basal plasma IL-6 correlating to higher physical activity level (27). ...
... In response to acute exercise, plasma IL-6 levels increase nonlinearly over time, peaking at the end of exercise and then falling to the pre-exercise level (27). By contrast, there is a negative association between basal plasma IL-6 levels and amount of regular physical activity, low basal plasma IL-6 correlating to higher physical activity level (27). Regular physical activity entails multiple adaptations including increased pre-exercise skeletal muscle glycogen content, increased oxidation of intramuscular triglycerides, and enhanced activity of key enzymes involved in ß-oxidation (28,29). ...
... Regular physical activity entails multiple adaptations including increased pre-exercise skeletal muscle glycogen content, increased oxidation of intramuscular triglycerides, and enhanced activity of key enzymes involved in ß-oxidation (28,29). Skeletal muscle consequently increases its capacity to oxidize fat and becomes less dependent on plasma glucose and muscle glycogen as substrates during exercise (27). For IL-6 gene transcription, preexercise intramuscular glycogen content is an important stimulus, and so transcription rates are higher when glycogen levels are lower (17, 18). ...
Full-text available
Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in young people. Although biologics now enable most children and adolescents with JIA to enjoy clinical remission, patients present lower physical activity and spend more time in sedentary behavior than their healthy counterparts. This impairment probably results from a physical deconditioning spiral initiated by joint pain, sustained by apprehension on the part of both the child and the child’s parents, and entrenched by lowered physical capacities. This in turn may exacerbate disease activity and lead to unfavorable health outcomes including increased risks of metabolic and mental comorbidities. Over the past few decades, there has been growing interest in the health benefits of increased overall physical activity as well as exercise interventions in young people with JIA. However, we are still far from evidence-based physical activity and / or exercise prescription for this population. In this review, we give an overview of the available data supporting physical activity and / or exercise as a behavioral, non-pharmacological alternative to attenuate inflammation while also improving metabolism, disease symptoms, poor sleep, synchronization of circadian rhythms, mental health, and quality of life in JIA. Finally, we discuss clinical implications, identify gaps in knowledge, and outline a future research agenda.
... Exercise has chronic cytokine-lowering effects, and regular physical activity elicits anti-inflammatory effects that account for decreased risk of chronic diseases (170,270). Although acute responses to exercise actually include elevated cytokine levels, including IL-6, IL-1β, and TNFα, numerous studies show that long-term adaptations to exercise indicate an overall decrease in inflammatory signaling (87,88,226,282,318). Importantly, physical activity status is the best predictor of inflammatory biomarker levels, specifically TNFα and IL-6, even compared to other factors such as age (202,285). ...
Type 2 diabetes is a systemic, multifactorial disease that is a leading cause of morbidity and mortality globally. Despite a rise in the number of available medications and treatments available for management, exercise remains a first-line prevention and intervention strategy due to established safety, efficacy, and tolerability in the general population. Herein we review the predisposing risk factors for, prevention, pathophysiology, and treatment of type 2 diabetes. We emphasize key cellular and molecular adaptive processes that provide insight into our evolving understanding of how, when, and what types of exercise may improve glycemic control. © 2023 American Physiological Society. Compr Physiol 13:1-27, 2023.
... In the study, a reduction of IL6 was found in the samples of the groups treated with exercise, mainly in the exercise groups performed on the treadmill. This may be because IL6 with an anti-inflammatory profile peaks during muscle contraction during exercise, followed by an important gradual decrease soon after the end of the activity (Fischer, 2006;Benatti and Pedersen, 2015). Thus, as the material for analysis of this cytokine was removed 48 h after the last exercise session, it is understood that the evaluated IL6 has a pro-inflammatory profile probably associated with the characteristics of osteoarthritic disease. ...
Full-text available
Introduction: Osteoarthritis (OA) is considered an inflammatory and degenerative joint disease, characterized by loss of hyaline joint cartilage and adjacent bone remodeling with the formation of osteophytes, accompanied by various degrees of functional limitation and reduction in the quality of life of individuals. The objective of this work was to investigate the effects of treatment with physical exercise on the treadmill and swimming in an animal model of osteoarthritis. Methods: Forty-eight male Wistar rats were divided (n=12 per group): Sham (S); Osteoarthritis (OA); Osteoarthritis + Treadmill (OA + T); Osteoarthritis + Swimming (OA + S). The mechanical model of OA was induced by median meniscectomy. Thirty days later, the animals started the physical exercise protocols. Both protocols were performed at moderate intensity. Forty-eight hours after the end of the exercise protocols, all animals were anesthetized and euthanized for histological, molecular, and biochemical parameters analysis. Results: Physical exercise performed on a treadmill was more effective in attenuating the action of pro-inflammatory cytokines (IFN-γ, TNF-α, IL1-β, and IL6) and positively regulating anti-inflammatories such as IL4, IL10, and TGF-β in relation to other groups. Discussion: In addition to maintaining a more balanced oxi-reductive environment within the joint, treadmill exercise provided a more satisfactory morphological outcome regarding the number of chondrocytes in the histological evaluation. As an outcome, better results were found in groups submitted to exercise, mostly treadmill exercise.
... Physical activity is one of the lifestyle factors that has been linked to a reduced chronic disease risk [7]. High levels of physical activity, reduced insulin resistance [8], improved lipoprotein profiles [9], and lowered interleukin (IL)-6 levels in the long-term [10], contribute to a lower chronic disease risk [11][12][13][14]. It is not well studied whether systemic changes are already visible in the basal state in healthy individuals with different habitual physical activity levels, reflected in differences in aerobic fitness. ...
Full-text available
Biomarkers are important in the assessment of health and disease, but are poorly studied in still healthy individuals with a (potential) different risk for metabolic disease. This study investigated, first, how single biomarkers and metabolic parameters, functional biomarker and metabolic parameter categories, and total biomarker and metabolic parameter profiles behave in young healthy female adults of different aerobic fitness and, second, how these biomarkers and metabolic parameters are affected by recent exercise in these healthy individuals. A total of 102 biomarkers and metabolic parameters were analysed in serum or plasma samples from 30 young, healthy, female adults divided into a high-fit (V̇O2peak ≥ 47 mL/kg/min, N = 15) and a low-fit (V̇O2peak ≤ 37 mL/kg/min, N = 15) group, at baseline and overnight after a single bout of exercise (60 min, 70% V̇O2peak). Our results show that total biomarker and metabolic parameter profiles were similar between high-fit and low-fit females. Recent exercise significantly affected several single biomarkers and metabolic parameters, mostly related to inflammation and lipid metabolism. Furthermore, functional biomarker and metabolic parameter categories corresponded to biomarker and metabolic parameter clusters generated via hierarchical clustering models. In conclusion, this study provides insight into the single and joined behavior of circulating biomarkers and metabolic parameters in healthy females, and identified functional biomarker and metabolic parameter categories that may be used for the characterisation of human health physiology.
... These results could be explained by the duration, intensity and type of exercise. Fisher [34] reported that post-exercise variations in IL-6 depend on the duration, intensity and type of exercise. ...
Das menschliche Immunsystem ist ein hoch komplexes Netzwerk von Zellen und Molekülen, das den Mensch frei von Infektionen und Krankheiten halten soll. Epidemiologische Studien belegen, dass ein körperlicher aktiver Lebensstil die Inzidenz übertragbarer (z. B. bakterieller und viraler Infektionen) und nicht-übertragbarer Krankheiten (z. B. Krebs, Arteriosklerosefolgeerkrankungen, Herz-Kreislauf-Erkrankungen, Diabetes, kognitive Beeinträchtigungen und Fettleibigkeit) verringert. Demzufolge hat körperliche Aktivität im Sinne von Übung, Training und (Leistungs-)Sport einen tiefgreifenden Einfluss auf die normale Funktion des Immunsystems. Die Immunkompetenz kann demnach durch regelmäßige körperliche Aktivität verbessert werden. Es hat sich gezeigt, dass die kardiorespiratorische Fitness und die regelmäßige körperliche Aktivität mit moderater bis anstrengender Intensität zum Beispiel die Immunantworten auf Impfungen verbessert, chronische Entzündungen und unterschiedliche Immunmarker bei verschiedenen Krankheitszuständen positiv beeinflussen kann, wie zum Beispiel Krebs-, HIV- und Herz-Kreislauf-Erkrankungen, Diabetes mellitus, kognitive Beeinträchtigungen und Fettleibigkeit. Die belastungsinduzierte immunologische Stressregulation, hervorgerufen durch körperliche Aktivität bei akuten Belastungen, induziert eine intensitätsabhängige biphasische Leukozytose (Lymphozyten und Neutrophile Granulozyten), begleitet von einer Umverteilung von Effektorzellen in die peripheren Gewebe. Diese immunregulatorischen Prozesse der unmittelbaren Sofortreaktion und der verzögerten immunologischen Regulation resultieren aus der Aktivierung des sympathischen Nervensystems (Freisetzung Katecholamine) und der Hypothalamus-Hypophyse-Nebennieren-Achse (Freisetzung Glukokortikoide) sowie der damit verbundenen erhöhten Blutzirkulation. Im Kontext dieser belastungsinduzierten immunologischen Regulation ist das Infektionsrisiko von Sporttreibenden ein klinisch-gesundheitliches und (leistungs-)sportrelevantes Thema. Es kann davon ausgegangen werden, dass körperliches Üben und Trainieren nicht per se das Risiko für eine Infektion der oberen Atemwege erhöht, sondern auch protektive Effekte einer verbesserten Immunantwort auf bakterielle und virale oder andere Antigene zu erwarten sind. Dafür ist eine Balance unterschiedlicher Faktoren (z. B. Schlaf, Ernährung, psychischer Stress, Überlastung) notwendig, welche ebenfalls die angeborene und adaptive Immunität beeinflussen. Darüber hinaus ist es durch regelmäßige körperliche Aktivität und Training möglich, das immunologische Altern und die damit verbundene veränderte Immunkompetenz positiv zu beeinflussen. Dieser Beitrag ist Teil der Sektion Sportmedizin, herausgegeben vom Teilherausgeber Holger Gabriel, innerhalb des Handbuchs Sport und Sportwissenschaft, herausgegeben von Arne Güllich und Michael Krüger.
Not all women who have a normal weight are healthy. There are three main types of unhealthy lean including metabolically unhealthy normal weight (MUNW), normal weight with central obesity (NWCO), and normal weight obesity (NWO). These unhealthy lean individuals have an increased risk for cardiometabolic disease and mortality compared to healthy lean, but often, they are undiagnosed, since their body weight is considered “normal”. Some associations between age, sex, ethnicity, genetics, and lifestyle factors with unhealthy lean have been described. Lifestyle interventions including diet and exercise may help to improve the health of these individuals. However, there are many gaps in the past literature regarding etiology, pathophysiology, and interventions, because this is an understudied area. Furthermore, there is a lack of consensus regarding the definition of different types of unhealthy lean.
Full-text available
Purpose: This study tested the hypothesis that antioxidant supplementation would attenuate plasma cytokine (IL-6, tumor necrosis factor (TNF)-α), and C-reactive protein (CRP) concentrations at rest and in response to exercise at 4300-m elevation. Methods: A total of 17 recreationally trained men were matched and assigned to an antioxidant (N = 9) or placebo (N = 8) group in a double-blinded fashion. At sea level (SL), energy expenditure was controlled and subjects were weight stable. Then, 3 wk before and throughout high altitude (HA), an antioxidant supplement (10,000 IU β-carotene, 200 IU α-tocopherol acetate, 250 mg ascorbic acid, 50 2g selenium, 15 mg zinc) or placebo was given twice daily. At HA, energy expenditure increased approximately 750 kcald-1 and energy intake decreased approximately 550 kcald-1, resulting in a caloric deficit of approximately 1200–1500 kcald-1. At SL and HA day 1 (HA1) and day HA13, subjects exercised at 55% of VO2peak until they expended approximately 1500 kcal. Blood samples were taken at rest, end of exercise, and 2, 4, and 20 h after exercise. Results: No differences were seen between groups in plasma IL-6, CRP, or TNF-! at rest or in response to exercise. For both groups, plasma IL-6 concentration was significantly higher at the end of exercise, 2, 4, and 20 h after exercise at HA1 compared with SL and HA13. Plasma CRP concentration was significantly elevated 20 h postexercise for both groups on HA1 compared to SL and HA13. TNF-α did not differ at rest or in response to exercise. Conclusion: Plasma IL-6 and CRP concentrations were elevated following exercise at high altitude on day 1, and antioxidant supplementation did not attenuate the rise in plasma IL-6 and CRP concentrations associated with hypoxia, exercise, and caloric deficit.
Full-text available
The authors wish to correct an error that appeared in the text. The corrected paragraph appears below. However, it is critically important to recognize that the CRP response is nonspecific and is triggered by many disorders unrelated to cardiovascular disease (Table 2). In using CRP for assessment of cardiovascular risk, it is therefore essential to clearly establish true base-line CRP values that are not distorted by either trivial or serious intercurrent pathologies. If the initial CRP result is in the low-risk range, less than 1 mg/l, a single measurement is sufficient, but if it is in the higher risk range, greater than about 2.5 mg/l, two or more serial samples taken at intervals of 1 week or more should be retest-ed until a stable base-line value is seen. If the CRP value persistently remains above 10 mg/l, indicating the presence of a significant acute-phase response, a full history and physical examination of the patient is indicated, ideally together with relevant investigations, to determine the cause and alleviate it if possible. Interestingly, chronic inflammatory conditions, such as rheumatoid arthritis and hemodialysis for end-stage renal failure, that are characterized by persistently elevated CRP concentrations in some individuals, are associated with premature cardiovascular disease.
The aim of this study was to investigate the potential role of adipose cytokines in the obesity-associated insulin resistance. To that end, we compared: 1) serum concentrations of interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalpha), and leptin in eight healthy lean control females and in android obese female without (n = 14) and with (n = 7) type 2 diabetes; and 2) the levels of these cytokines both in serum and in sc adipose tissue in the 14 obese nondiabetic women before and after 3 weeks of a very low-calorie diet (VLCD). As compared with lean controls, obese nondiabetic and diabetic patients were more insulin resistant and presented increased values for leptin, IL-6, TNFalpha, and C-reactive protein. In the whole group, IL-6 values were more closely related to the parameters evaluating insulin resistance than leptin or TNFalpha values. VLCD resulted in weight loss and decreased body fat mass (approximately 3 kg). Insulin sensitivity was improved with no significant change in both serum and adipose tissue TNFalpha levels. In contrast, VLCD induced significant decreases in IL-6 and leptin levels in both adipose tissue and serum. These results suggest that, as for leptin, circulating IL-6 concentrations reflect, at least in part, adipose tissue production. The reduced production and serum concentrations after weight loss could play a role in the improved sensitivity to insulin observed in these patients.
• Prolonged exercise results in a progressive decline in glycogen content and a concomitant increase in the release of the cytokine interleukin-6 (IL-6) from contracting muscle. This study tests the hypothesis that the exercise-induced IL-6 release from contracting muscle is linked to the intramuscular glycogen availability. • Seven men performed 5 h of a two-legged knee-extensor exercise, with one leg with normal, and one leg with reduced, muscle glycogen content. Muscle biopsies were obtained before (pre-ex), immediately after (end-ex) and 3 h into recovery (3 h rec) from exercise in both legs. In addition, catheters were placed in one femoral artery and both femoral veins and blood was sampled from these catheters prior to exercise and at 1 h intervals during exercise and into recovery. • Pre-exercise glycogen content was lower in the glycogen-depleted leg compared with the control leg. Intramuscular IL-6 mRNA levels increased with exercise in both legs, but this increase was augmented in the leg having the lowest glycogen content at end-ex. The arterial plasma concentration of IL-6 increased from 0.6 ± 0.1 ng l−1 pre-ex to 21.7 ± 5.6 ng l−1 end-ex. The depleted leg had already released IL-6 after 1 h (4.38 ± 2.80 ng min−1 ( P −1). A significant net IL-6 release was not observed until 2 h in the control leg. • This study demonstrates that glycogen availability is associated with alterations in the rate of IL-6 production and release in contracting skeletal muscle.
The purpose of this randomized study was to measure the influence of vitamin C (n = 15 runners) compared with placebo (n = 13 runners) supplementation on oxidative and immune changes in runners competing in an ultramarathon race. During the 7-day period before the race and on race day, subjects ingested in randomized, double-blind fashion 1,500 mg/day vitamin C or placebo. On race day, blood samples were collected 1 h before race, after 32 km of running, and then again immediately after race. Subjects in both groups maintained an intensity of ∼75% maximal heart rate throughout the ultramarathon race and ran a mean of 69 km (range: 48-80 km) in 9.8 h (range: 5-12 h). Plasma ascorbic acid was markedly higher in the vitamin C compared with placebo group prerace and rose more strongly in the vitamin C group during the race (post-race: 3.21 ± 0.29 and 1.28 ± 0.12 μg/100 μl, respectively, P < 0.001). No significant group or interaction effects were measured for lipid hydroperoxide, F2-isoprostane, immune cell counts, plasma interleukin (IL)-6, IL-10, IL-1-receptor antagonist, or IL-8 concentrations, or mitogen-stimulated lymphocyte proliferation and IL-2 and IFN-γ production. These data indicate that vitamin C supplementation in carbohydrate-fed runners does not serve as a countermeasure to oxidative and immune changes during or after a competitive ultramarathon race.