Elsevier

Immunology Letters

Volume 99, Issue 1, 15 June 2005, Pages 136-140
Immunology Letters

Short communication
Lack of relationship between interleukin-6 and CRP levels in healthy male athletes

https://doi.org/10.1016/j.imlet.2005.02.006Get rights and content

Abstract

Interleukin-6 (IL-6) is the main cytokine involved in the induction of acute phase response, which includes synthesis of certain proteins in the liver, one of which is C-reactive protein (CRP).

The aim of this study was to assess the impact of IL-6 released during physical exercise on CRP generation in healthy male athletes.

Fourteen young cyclists were enrolled in the study, which involves the performance of strenuous physical exercise. Serum levels of IL-6 and CRP were measured at rest before exercise, and immediately after and 2 h after cessation of exercise. IL-6 level was increased 2.42-fold immediately after, and 21.67-fold 2 h after exercise. Serum CRP level did not change significantly over the course of observation: it was 3.25 mg/dl before, 2.36 mg/dl immediately after and 2.71 mg/dl 2 h after exercise and unrelated to IL-6 level. No correlation between serum levels of IL-6 and CRP was observed during the period of observation.

We conclude that under certain circumstances, acute, pulsatile release of IL-6 does not stimulate synthesis of CRP.

Introduction

Interleukin-6 (IL-6) is a 22–27 kDa polypeptide synthesized and secreted from activated monocytes, macrophages, fibroblasts, endothelial cells and adipocytes in response to various stimuli such as bacterial endotoxins, physical exercise, tissue damage and oxidative stress. It has been shown that pro-inflammatory cytokines (IL-1 and TNF-α) induce the synthesis of IL-6 [1].

IL-6 exerts biological effects through a receptor complex consisting of IL-6 receptor (IL-6R) and signal-transducing subunit (gp130). Soluble forms of two components of the above receptor influence IL-6 activity. sIL-6R prolongs the half–life of IL-6 and thereby prolongs its activity, while the soluble form of gp130 acts as an antagonist of IL-6 [1].

Notably, although most cytokines act via autocrine/paracrine mechanisms, IL-6 reaches its target organs via circulating blood. Effects of IL-6 may thus occur at locations distant from its source.

IL-6 and its soluble receptors are believed to be central regulators of immunological and inflammatory process in humans. The IL-6 system promotes activation and proliferation of lymphocytes, differentiation of B cells, leukocyte recruitment, neural cell survival and differentiation, activation of the hypothalamic-pituitary-adrenal axis, and expansion of hematopoietic progenitors [2], [3].

IL-6 also induces acute phase responses in the liver, which include the synthesis of several unique hepatic proteins in patients with infection, trauma, inflammatory processes and some malignances. These proteins are not produced in healthy individuals [2], [4].

C-reactive protein (CRP) is an example of an acute phase protein and is a sensitive marker of inflammation regardless of etiology. It has been believed that the synthesis of CRP is induced by both IL-6 and IL-1. However, Eklund et al. recently found that basal CRP level in healthy individuals is regulated by IL-1β, and not by the genetics of IL-6 [5].

Acute phase responses are nonspecific. Measurements of serum IL-6, TNF-α or IL-1 receptor antagonists may be used as indicators of acute phase responses. However, these measurements are not easy to perform in clinical practice, whereas CRP can easily be determined in the majority of hospital laboratories.

It has recently been emphasized that chronic inflammation plays an important role in the pathogenesis of various pathological states such as cardiovascular disease, obesity, diabetes, cancer, and malnutrition. For example, there is strong evidence that IL-6 is a significant pro-atherogenic cytokine [6]. A recent study showed that infusion of recombinant IL-6 exacerbates early atherosclerosis in apo-E-deficient mice, and elevated circulating IL-6 levels have been found to be independently associated with progressive carotid atherosclerosis in hemodialyzed patients [7], [8]. Increased levels of IL-6 and CRP are also found in patients with de-compensated congestive heart failure [9].

Synthesis of acute phase proteins in the liver following pro-inflammatory cytokine stimulation is associated with higher risk of cardiovascular events as well [6], [10], [11]. It has been shown that CRP promotes vascular inflammation and thrombosis and is involved in the progression of atherosclerosis. Increased CRP level is thus associated with increased cardiac morbidity [10], [11].

Several studies have suggested that physical exercise induces muscle damage and a complex cascade of non-specific inflammatory responses. Several studies have been performed to test the hypotheses that local cytokine production takes place in response to mechanically damage of myofibrils or disruption of connective tissue in muscle, and that local cytokine responses may initiate systemic inflammatory responses. IL-6 mRNA is detectable in skeletal muscle after prolonged, intense exercise, indicating that IL-6 is produced locally in the skeletal muscle [12], [13].

The goal of our study was to assess the impact of IL-6 released during physical exercise on CRP generation in healthy young male athletes.

Section snippets

Subjects

Fourteen male cyclists participated in the study. The mean age of participants was 18 ± 0.5 years. Characteristics of subjects enrolled in the study are shown in Table 1.

The experimental protocol was approved by the Ethics Committee of the Medical University of Warsaw and all subjects were informed of the risks and purposes of the study before their written consent was obtained.

The subjects performed graded cycling on a running track (Saturn, H-P Cosmos, Nussdorf, Germany) to exhaustion. The

Results

Serum IL-6 level significantly increased from 0.5 pg/ml before to 1.21 pg/ml (2.42-fold) immediately after, and to 10.83 pg/ml (21.67-fold) 2 h after exercise (Table 2).

Serum CRP concentration exhibited no significant change: it was 3.25 mg/dl before, 2.36 mg/dl immediately after, and 2.71 mg/dl 2 h after exercise and unrelated to IL-6 level (Table 2).

No correlation was observed between serum levels of IL-6 and CRP during the period of observation (pre-exercise status p = 0.693 and correlation r = −0.116;

Discussion

The major finding of our study was that C-reactive protein did not increase in parallel with serum level of interleukin-6 in young male cyclists after strenuous exercise.

Some authors have found that circulating level of IL-6 is transiently but promptly elevated (up to 100-fold) in response to various types of physical exercise [14], [15]. Haahr et al. [16] found that the production of IL-6 increased significantly 2 h after exercise, consistent with our results, and that production of IL-1 was

Acknowledgement

We would like to thank Dr. Paul Kretchmer ([email protected]) at San Francisco Edit for his assistance in editing this manuscript.

References (33)

  • M.C. Wolvekamp et al.

    Interleukin-6: historical background, genetics and biological significance

    Immunol Lett

    (1990)
  • M. Albert et al.

    Effect of physical activity on serum C-reactive protein

    Am J Cardiol

    (2004)
  • H.K. Yip et al.

    levels and values of serum high-sensitivity C-reactive protein within 6 h after the onset of acute myocardial infarction

    Chest

    (2004)
  • R. Pecoits-Filho et al.

    Update on interleukin-6 and its role in chronic renal failure

    Nephrol Dial Transplant

    (2003)
  • T. Taga et al.

    Gp130 and the interleukin-6 family of cytokines

    Annu Rev Immunol

    (1997)
  • P.B. Sehgal

    Interleukin-6: a regulator of plasma protein gene expression in hepatic and non-hepatic tissue

    Mol Biol Med

    (1990)
  • C. Eklund et al.

    Interleukin 1β gene polymorphism is associated with baseline C-reactive protein levels in healthy individuals

    Eur Cytokine Netw

    (2003)
  • E.A. Bermudez et al.

    Interrelationship among circulating interleukin-6, C-reactive protein, and traditional cardiovascular risk factors in women

    Arterioscler Thromb Vasc Biol

    (2002)
  • S.A. Huber et al.

    Interleukine-6 exacerbates early atherosclerosis in mice

    Arterioscler Thromb Vasc Biol

    (1999)
  • P. Steinvinkel et al.

    Elevated interleukin-6 predicts progressive artery atherosclerosis in dialysis patients association with Chlamydia pneumoniae seropositivity

    Am J Kidney Dis

    (2002)
  • Y. Sato et al.

    Serial circulating concentration of C-reactive protein, interleukine (IL)-4, IL-6 in patients with acute left hearth decompensation

    Clin Cardiol

    (1999)
  • W. Koenig

    C-reactive protein and cardiovascular risk: an update on what is going on in cardiology

    Nephrol Dial Transplant

    (2003)
  • C. Byrne et al.

    Elevated white cell count in acute coronary syndromes: relationship to variants in inflammatory and thrombotic genes

    BMC Med Genet

    (2004)
  • K. Ostrowski et al.

    Evidence that interleukin-6 is produced in human skeletal muscle during prolonged running

    J Physiol

    (1998)
  • B.K. Pedersen et al.

    Muscle-derived interleukin-6: lipolytic, anti-inflammatory and immune regulatory effects

    Pflugers Arch

    (2003)
  • K. Ostrowski et al.

    Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans

    J Physiol

    (1999)
  • Cited by (37)

    • Exercise and immunity

      2022, Exercise to Prevent and Manage Chronic Disease Across the Lifespan
    • Point of care testing of sports biomarkers: Potential applications, recent advances and future outlook

      2021, TrAC - Trends in Analytical Chemistry
      Citation Excerpt :

      Amongst these cytokines, IL-6 is the highest in concentration in blood plasma and can elevate up to 100 times from pre-exercise levels [103]. The release of pro-inflammatory cytokines also induces the secretion of C-Reactive Protein (CRP), which is used in conjunction as another important inflammation and injury risk marker [104]. However, similar to S-100B concussion marker, these cytokines also have significant inter-individual variations, and hence it is difficult to establish a common baseline.

    • Plasma microRNA-155-5p is increased among patients with chronic kidney disease and nocturnal hypertension

      2017, Journal of the American Society of Hypertension
      Citation Excerpt :

      In the context of pro-inflammatory actions of miR-155-5p, we found no association between CRP and miR-155-5p in our study population. Some reports suggested that CRP does not rise in every proinflammatory condition, that is, in the study by Czarkowska-Paczek et al,50 a rise in IL-6 (a strong inducer of CRP synthesis) concentrations were not associated with CRP elevation in the subset of young athletes subjected to strenuous exercise. Therefore, CKD patients, despite tendency toward increased IL-6 concentrations may not necessarily present increased CRP values.

    • Nutrient patterns and chronic inflammation in a cohort of community dwelling middle-aged men

      2017, Clinical Nutrition
      Citation Excerpt :

      Although it is believed to be induced in the liver by IL-1 and IL-6 as the response to acute infection, CRP has been suggested to be regulated by IL-1 but not IL-6 in healthy subjects [32]. Lack of relationship between IL-6 and CRP has also been suggested in male athletes after exercise [33], suggesting IL-6 may be involved more in metabolic effects than inflammatory responses in certain circumstances. Moreover, IL-6 has shorter plasma half-time [34] and is more susceptible to diurnal variation [35] compared with CRP.

    • Correlation of Interleukin-6 levels and lectins during Schistosoma haematobium infection

      2015, Cytokine
      Citation Excerpt :

      Notably, we observed an inverse correlation of IL-6 with MBL and ficolin-2, but not with CL-K1 serum levels, both in seropositive and seronegative controls. As healthy individuals are not exposed to inflammatory stimuli, the negative correlation of IL-6 levels with the lectins MBL and ficolin-2 may be explained [29]. However, the exact mechanism responsible for the inverse correlation of MBL and ficolin-2 with IL-6 and the absence of any correlation of IL-6 with CL-K1 in healthy individuals needs to be explored further.

    • Longitudinal changes in serum proinflammatory markers across pregnancy and postpartum: Effects of maternal body mass index

      2014, Cytokine
      Citation Excerpt :

      IL-6 release does not result in concomitant CRP production in certain circumstances. For example, in response to acute exercise, substantial increases in serum IL-6 do not result in corresponding increases in CRP [53]. In addition to instigating the acute phase response, IL-6 serves multiple functions including effects on metabolism, regulation of bone homeostasis, and pain regulation [54].

    View all citing articles on Scopus
    View full text