Short communicationLack of relationship between interleukin-6 and CRP levels in healthy male athletes
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.
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