| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1The Copenhagen Muscle Research Centre and 2The Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark
Submitted 19 February 2003 ; accepted in final form 20 April 2003
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
|---|
140 pg/ml, corresponding to the levels obtained during strenuous
exercise. The infusion of rhIL-6 did not induce enhanced levels of the
proinflammatory cytokine TNF-
but enhanced the plasma levels of the two
anti-inflammatory cytokines IL-1 receptor agonist (IL-1ra) and IL-10 compared
with saline infusion. In addition, C-reactive protein increased 3 h
post-rhIL-6 infusion and was further elevated 16 h later compared with saline
infusion. rhIL-6 induced increased levels of plasma cortisol and,
consequently, an increase in circulating neutrophils and a decrease in the
lymphocyte number without effects on plasma epinephrine, body temperature,
mean arterial pressure, or heart rate. In conclusion, this study demonstrates
that physiological concentrations of IL-6 induce an anti-inflammatory rather
than an inflammatory response in humans and that IL-6, independently of
TNF-, enhances the levels not only of IL-1ra but also of IL-10.
Furthermore, IL-6 induces an increase in cortisol and, consequently, in
neutrocytosis and late lymphopenia to the same magnitude and with the same
kinetics as during exercise, suggesting that muscle-derived IL-6 has a central
role in exercise-induced leukocyte trafficking.
cytokines; C-reactive protein; tumor necrosis factor-; neutrophils and lymphocytes; interleukin-1 receptor agonist
production. Studies in IL-6 knockout mice have
demonstrated that these mice possess a compromised ability to control the
proinflammatory cytokine response to injected endotoxin
(35). Recently, we
demonstrated that infusion of recombinant human (rh)IL-6 to healthy volunteers
inhibited low-grade endotoxin-induced TNF- production
(25a). A number of
epidemiological studies have shown increased levels of both TNF- and
IL-6 in aging (4), in obese
individuals (2), and in
patients with type 2 diabetes
(13,
17,
24,
34). Furthermore, plasma
concentrations of IL-6 have been shown to predict total and cardiovascular
mortality in population-based studies
(25). It is, however, not
known whether chronically elevated levels of IL-6 are causally related to
atherosclerosis, obesity, and insulin resistance. On the basis of evidence
that IL-6 exerts anti-inflammatory effects, it is likely that the elevated
plasma IL-6 found in these individuals represents low-grade inflammation,
rather than its cause.
We have used exercise as a model for the study of metabolic and
immunological interactions (for reviews see Refs.
22 and
23). During strenuous
exercise, several cytokines transiently increase in plasma along with changes
in circulating immune cells
(21). The increase in IL-6
during exercise precedes that of other cytokines examined
(20). Therefore, IL-6 is
likely to play a central role in the cytokine cascade. The IL-6 gene is
expressed within and released from contracting muscles
(30), especially when
intramuscular glycogen is low
(14,
26). There is evidence to
suggest that one function of muscle-derived IL-6 during exercise is to work as
a hormone by increasing substrate mobilization
(15). In addition,
muscle-derived IL-6 may also induce anti-inflammatory effects. High plasma
concentrations of IL-6 induce the expression of the IL-1 receptor antagonist
(ra) (33), a cytokine that
antagonizes the effects of the proinflammatory cytokine IL-1
(8). Whether IL-6,
independently of TNF-, induces IL-10, one of the other major
anti-inflammatory cytokines, is not known. Injection of IL-6 into humans
increases plasma adrenocorticotropic hormone and plasma cortisol
(3,
31). Moreover, both the
pituitary corticotrophs and adrenocortical cells express IL-6 receptors, and
IL-6 is able to induce an increase in cortisol both directly and indirectly
(3).
Acute elevations in plasma IL-6 either by infusion of IL-6 or by exercise are therefore likely to stimulate the anti-inflammatory environment, thereby reducing any ongoing inflammatory processes in the host. These same subjects, however, might consequently also experience immune impairment and enhanced susceptibility to infections.
Exercise induces highly stereotyped changes in leukocyte subpopulations. Thus the number of neutrophils increases during and after exercise, whereas the lymphocyte number increases during exercise and decreases in the postexercise period (22). Whereas the initial changes can be ascribed to the effect of catecholamines (29), the prolonged changes in leukocyte numbers are most likely mediated through an effect of muscle-derived IL-6 on cortisol production.
In the present study, a low dose of rhIL-6 or saline was infused for 3 h
into healthy humans. The plasma IL-6 levels obtained were comparable to those
observed during strenuous prolonged exercise
(21). Any changes in cortisol,
lymphocytes, neutrophils, C-reactive protein (CRP), IL-10, IL-1ra, and
TNF- were measured in the blood during the infusion and in the hours
after it. We hypothesized that IL-6 infusion would induce an increase in
plasma IL-1ra and IL-10, plasma CRP, and cortisol as well as a consequent
increase in neutrophil and decrease in lymphocyte numbers, without any changes
in TNF-.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
|---|
Protocol. Subjects reported to the laboratory at 0700 after an
overnight fast. They voided, changed into appropriate hospital attire, and
remained supine during the entire experiment. They were permitted to consume
only water during the experiment. After 10 min, the femoral arteries of both
legs were cannulated as previously described
(26). One femoral arterial
catheter was used for the infusion of rhIL-6 or saline. The other arterial
line was used for blood sampling. At 1000, the 3-h infusion of rhIL-6 or
saline commenced.
IL-6 infusates. The rhIL-6 (Sandoz, Basel, Switzerland) was infused in a dose lower than that reported to be safe in other studies (31). The IL-6 doses were chosen on the basis of pilot experiments. We aimed to reach plasma levels of IL-6 characteristic of intense exercise or low-grade inflammation. The rate of rhIL-6 infusion was 30 µg/h, with saline used as a vehicle. Saline was infused during the control trial.
Blood analysis. Blood samples for IL-6, IL-10, IL-1ra, and
TNF- were measured by high-sensitivity ELISA, as previously described
(21), and CRP, blood
lymphocytes, and neutrophils were measured by standard laboratory procedures.
Plasma epinephrine was measured by HPLC, and plasma cortisol (Diagnostic
Products, Los Angeles, CA) was analyzed by radioimmunoassay, as previously
described (27).
Physiological variables. Heart rate and mean arterial pressure (MAP) were measured every 60 min by use of electrocardiography and sphygmomanometry, respectively. Temperature was also measured at these time points via a tympanic probe.
Statistics. All data are presented as means ± SE;
n = 6. Plasma IL-6, IL-1ra, IL-10, and TNF- values were log
transformed to obtain a normal distribution. To analyze changes over time and
between groups, a two-way repeated-measures analysis of variance (RM-ANOVA)
was used. If such analysis revealed significant differences, a Newman-Keuls
post hoc test was used to locate the specific differences. P <
0.05 was accepted as significant.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
|---|
4 and 140 pg/ml, respectively. At the cessation of
the rhIL-6 infusion, plasma IL-6 declined rapidly toward preinfusion levels
within the first hour. Plasma epinephrine, heart rate, MAP, and temperature
were not affected by IL-6 infusion or time, as shown in
Table 1.
|
Infusion of rhIL-6 did not affect the levels of TNF- in the plasma
(Fig. 1A). The two
cytokines IL-10 and IL-1ra significantly increased (P < 0.05)
during the rhIL-6 infusion compared with saline and preinfusion, with
8-fold and 26-fold increases, respectively. At the cessation of the
infusion, the plasma concentrations of both cytokines declined toward basal
levels (Fig. 1, B and
C). Plasma CRP was increased (P < 0.05) 3 h
after the cessation of the rhIL-6 infusion, reaching 22 ± 3 mg/l 16 h
later (Fig. 2).
|
|
Plasma cortisol increased (P < 0.05) during rhIL-6 infusion and declined toward basic levels at the cessation of infusion (Fig. 3A). The number of circulating neutrophils increased (P < 0.05) during the rhIL-6 infusion, peaking 2 h into the infusion (13.1 ± 0.8 x 109/l) compared with control (5.5 ± 0.7 x 109/l). The next day, circulating neutrophils were back to preinfusion numbers (Fig. 3B). The lymphocyte number declined modestly (P < 0.05) during the rhIL-6 infusion but did not change during saline infusion (Fig. 3C).
|
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
|---|
, plasma catecholamines,
temperature, MAP, or heart rate, thus indicating that an important function of
IL-6 is to limit the potentially injurious effects of sustained
inflammation.
IL-6 is known to inhibit an endotoxin-associated increase in TNF- in
humans (25a). Because we found
that IL-6 infusion did not decrease the basal plasma levels of TNF-, it
is possible that IL-6 influences circulating levels of TNF- by
inhibiting dynamic TNF- production or release. However, we cannot
exclude the possibility that treatment with IL-6 for days would have an effect
on the basal plasma levels of TNF-, especially in individuals who have
higher basal plasma levels of TNF-, such as aged or obese subjects or
patients with type 2 diabetes.
To our knowledge, this is the first study to demonstrate that IL-6,
independently of TNF-, induces the release of IL-10. Others have
demonstrated that supraphysiological doses of IL-6 concentrations induce
IL-1ra in humans (33). The
only known biological role of IL-1ra is its ability to bind to the IL-1
receptor and thereby inhibit the function(s) of IL-1 and IL-1
(8). IL-1ra is mainly produced
by monocytes and macrophages after stimulation with lipopolysaccharide
(8) or the cytokines IL-4,
IL-6, IL-10, and IL-14 (7).
IL-10 is produced by Th2 lymphocytes, monocytes, and B cells, and it inhibits
several immune pathways. Moreover, IL-10 is a potent inhibitor of Th1-,
monocyte-, and macrophage-derived cytokines
(19). In addition, IL-10
attenuates the surface expression of TNF- receptors
(6,
12). The finding that plasma
CRP was higher 16 h postinfusion than after 3 h demonstrates a prolonged
anti-inflammatory effect of the rhIL-6 infusion. CRP and other acute-phase
proteins are anti-inflammatory and immunosuppressive mediators
(32). Moreover, in in vivo
models, CRP can inhibit polymorphonuclear (PMN) leukocyte infiltration
(11) and attenuate vascular
injury induced by stimulated PMN leukocytes
(1). In an in vitro model
(10), CRP inhibits
intracellular calcium mobilization and superoxide production by alveolar
macrophages.
The IL-6-induced increase in plasma cortisol is in agreement with previous findings (3, 31); therefore, the increase in circulating neutrophils found in this study is likely to be caused by the increase in plasma cortisol. Cortisol increases the circulating pool of neutrophils by inhibiting their ability to bind to the endothelial membrane (5) and to infiltrate into the tissue. Hence, the increased neutrophil number during rhIL-6 infusion is a sign of anti-inflammatory cortisol action. Exercise increases circulating neutrophils to a similar extent (29). It is therefore likely that muscle-derived IL-6 mediates this effect. A small decrease in the circulating pool of lymphocytes toward the end of rhIL-6 infusion supports the observation that the late lymphopenia seen during the recovery from exercise (29) may also be caused by IL-6. Exercise-induced disappearance of type 1 cytokine-producing cells from the circulation (28) may be related to elevated levels of IL-10. Also, the plasma IL-1ra and IL-10 increases seen during exercise (21) are likely to be mediated by IL-6.
In conclusion, this study demonstrates that physiological concentrations of
IL-6 induce an anti-inflammatory rather than a proinflammatory response in
humans and that IL-6, independently of TNF-, enhances the levels not
only of IL-1ra but also of IL-10. Furthermore, IL-6 stimulates cortisol
release and thus produces neutrocytosis and lymphopenia of the same magnitude
and pattern as are seen during intense exercise. This suggests that
muscle-derived IL-6, in addition to its metabolic effects, plays a key role in
exercise-induced leukocyte trafficking.
|
DISCLOSURES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
|---|
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
|---|
production in humans.
FASEB J 17:
884–886, 2003.This article has been cited by other articles:
|
|
 |
|
  B. K. Pedersen Edward F. Adolph Distinguished Lecture: Muscle as an endocrine organ: IL-6 and other myokines J Appl Physiol, October 1, 2009; 107(4): 1006 - 1014. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. K. Pedersen and M. A. Febbraio Muscle as an Endocrine Organ: Focus on Muscle-Derived Interleukin-6 Physiol Rev, October 1, 2008; 88(4): 1379 - 1406. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. A. Selkirk, T. M. McLellan, H. E. Wright, and S. G. Rhind Mild endotoxemia, NF-{kappa}B translocation, and cytokine increase during exertional heat stress in trained and untrained individuals Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2008; 295(2): R611 - R623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Kallio, M. Kolehmainen, D. E Laaksonen, L. Pulkkinen, M. Atalay, H. Mykkanen, M. Uusitupa, K. Poutanen, and L. Niskanen Inflammation markers are modulated by responses to diets differing in postprandial insulin responses in individuals with the metabolic syndrome Am. J. Clinical Nutrition, May 1, 2008; 87(5): 1497 - 1503. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Franzoso, C. Mazzon, M. Sztukowska, P. Cecchini, T. Kasic, B. Capecchi, R. Tavano, and E. Papini Human monocytes/macrophages are a target of Neisseria meningitidis Adhesin A (NadA) J. Leukoc. Biol., May 1, 2008; 83(5): 1100 - 1110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Meador, C. P. Krzyszton, R. W. Johnson, and K. A. Huey Effects of IL-10 and age on IL-6, IL-1{beta}, and TNF-{alpha} responses in mouse skeletal and cardiac muscle to an acute inflammatory insult J Appl Physiol, April 1, 2008; 104(4): 991 - 997. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Marsland, P. J. Gianaros, A. A. Prather, J. R. Jennings, S. A. Neumann, and S. B. Manuck Stimulated Production of Proinflammatory Cytokines Covaries Inversely With Heart Rate Variability Psychosom Med, October 1, 2007; 69(8): 709 - 716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. K. Pedersen, T. C. A. Akerstrom, A. R. Nielsen, and C. P. Fischer Role of myokines in exercise and metabolism J Appl Physiol, September 1, 2007; 103(3): 1093 - 1098. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hamer and A. Steptoe Association Between Physical Fitness, Parasympathetic Control, and Proinflammatory Responses to Mental Stress Psychosom Med, September 1, 2007; 69(7): 660 - 666. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. K. Pedersen State of the Art Reviews: Health Benefits Related to Exercise in Patients With Chronic Low-Grade Systemic Inflammation American Journal of Lifestyle Medicine, August 1, 2007; 1(4): 289 - 298. [Abstract] [PDF]
|
|
|
|
|
|
M. Gleeson Immune function in sport and exercise J Appl Physiol, August 1, 2007; 103(2): 693 - 699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-S. Wang, H.-Y. Lin, M.-L. Cheng, and M.-K. Wong Chronic intermittent hypoxia modulates eosinophil- and neutrophil-platelet aggregation and inflammatory cytokine secretion caused by strenuous exercise in men J Appl Physiol, July 1, 2007; 103(1): 305 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Flynn, B. K. McFarlin, and M. M. Markofski State of the Art Reviews: The Anti-Inflammatory Actions of Exercise Training American Journal of Lifestyle Medicine, May 1, 2007; 1(3): 220 - 235. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Taudorf, K. S. Krabbe, R. M. G. Berg, B. K. Pedersen, and K. Moller Human Models of Low-Grade Inflammation: Bolus versus Continuous Infusion of Endotoxin Clin. Vaccine Immunol., March 1, 2007; 14(3): 250 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S. Redwine, P. J. Mills, S. Hong, T. Rutledge, V. Reis, A. Maisel, and M. R. Irwin Cardiac-related Hospitalization and/or Death Associated With Immune Dysregulation and Symptoms of Depression in Heart Failure Patients Psychosom Med, January 1, 2007; 69(1): 23 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Nemet, A. Eliakim, F. Zaldivar, and D. M. Cooper Effect of rhIL-6 infusion on GH->IGF-I axis mediators in humans Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2006; 291(6): R1663 - R1668. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. W. Timmons, M. J. Hamadeh, and M. A. Tarnopolsky No effect of short-term 17beta-estradiol supplementation in healthy men on systemic inflammatory responses to exercise Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2006; 291(2): R285 - R290. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Zieker, E. Fehrenbach, J. Dietzsch, J. Fliegner, M. Waidmann, K. Nieselt, P. Gebicke-Haerter, R. Spanagel, P. Simon, A. M. Niess, et al. cDNA microarray analysis reveals novel candidate genes expressed in human peripheral blood following exhaustive exercise Physiol Genomics, November 17, 2005; 23(3): 287 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Bruunsgaard Physical activity and modulation of systemic low-level inflammation J. Leukoc. Biol., October 1, 2005; 78(4): 819 - 835. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Bisoendial, J. Kastelein, and E. Stroes Letter to the Editor: In response to van den Berg et al: Circ. Res., September 30, 2005; 97(7): e71 - e71. [Full Text] [PDF]
|
|
|
|
|
|
B. W. Timmons, M. J. Hamadeh, M. C. Devries, and M. A. Tarnopolsky Influence of gender, menstrual phase, and oral contraceptive use on immunological changes in response to prolonged cycling J Appl Physiol, September 1, 2005; 99(3): 979 - 985. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Plomgaard, P. Keller, C. Keller, and B. K. Pedersen TNF-{alpha}, but not IL-6, stimulates plasminogen activator inhibitor-1 expression in human subcutaneous adipose tissue J Appl Physiol, June 1, 2005; 98(6): 2019 - 2023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. W. Petersen and B. K. Pedersen The anti-inflammatory effect of exercise J Appl Physiol, April 1, 2005; 98(4): 1154 - 1162. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J Scharhag, T Meyer, H H W Gabriel, B Schlick, O Faude, W Kindermann, and R J Shephard Does prolonged cycling of moderate intensity affect immune cell function? * Commentary Br. J. Sports Med., March 1, 2005; 39(3): 171 - 177. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. P. Fischer, N. J. Hiscock, M. Penkowa, S. Basu, B. Vessby, A. Kallner, L.-B. Sjoberg, and B. K. Pedersen Supplementation with vitamins C and E inhibits the release of interleukin-6 from contracting human skeletal muscle J. Physiol., July 15, 2004; 558(2): 633 - 645. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Krogh-Madsen, K. Moller, F. Dela, G. Kronborg, S. Jauffred, and B. K. Pedersen Effect of hyperglycemia and hyperinsulinemia on the response of IL-6, TNF-{alpha}, and FFAs to low-dose endotoxemia in humans Am J Physiol Endocrinol Metab, May 1, 2004; 286(5): E766 - E772. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Krogh-Madsen, P. Plomgaard, P. Keller, C. Keller, and B. K. Pedersen Insulin stimulates interleukin-6 and tumor necrosis factor-{alpha} gene expression in human subcutaneous adipose tissue Am J Physiol Endocrinol Metab, February 1, 2004; 286(2): E234 - E238. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
