Elevation of IL-6 Solely Is Not Sufficient to Infer Systemic Inflammation

Abstract

In an excellent study in CHEST (July 2010), Sabit et al1Sabit R Thomas P Shale DJ Collins P Linnane SJ The effects of hypoxia on markers of coagulation and systemic inflammation in patients with COPD.Chest. 2010; 138: 47-51Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar showed that a 2-h hypoxic challenge in patients with mild COPD who are clinically stable results in an elevation of serum IL-6 and some coagulation markers, such as prothrombin activation fragments 1 + 2 and thrombin-antithrombin complex. The authors concluded that a strong association exists between hypoxia, coagulation activation, and systemic inflammation and that patients with COPD may be at increased risk of VTE during air travel. However, elevation of IL-6 solely cannot be used to infer the presence of systemic inflammation due to the pleiotropic action of IL-6 involving a variety of systems and diseases. IL-6 has been mostly studied in the context of the acute inflammatory response, although growing evidence shows IL-6 also plays a vital role in the pathogenesis of aging and chronic disease.2Maggio M Guralnik JM Longo DL Ferrucci L Interleukin-6 in aging and chronic disease: a magnificent pathway.J Gerontol A Biol Sci Med Sci. 2006; 61: 575-584Crossref PubMed Scopus (465) Google Scholar In addition, IL-6 is also a “myokine,” a cytokine produced from muscle, and is elevated in response to exercise.3Pedersen BK Febbraio MA Muscle as an endocrine organ: focus on muscle-derived interleukin-6.Physiol Rev. 2008; 88: 1379-1406Crossref PubMed Scopus (1435) Google Scholar, 4Steensberg A van Hall G Osada T Sacchetti M Saltin B Klarlund Pedersen B Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6.J Physiol. 2000; 529: 237-242Crossref PubMed Scopus (734) Google Scholar, 5Fischer CP Interleukin-6 in acute exercise and training: what is the biological relevance?.Exerc Immunol Rev. 2006; 12: 6-33PubMed Google Scholar Previous studies have demonstrated IL-6 levels can increase up to 100-fold during exercise, in a duration- and intensity-dependent manner.6Ostrowski K Hermann C Bangash A Schjerling P Nielsen JN Pedersen BK A trauma-like elevation of plasma cytokines in humans in response to treadmill running.J Physiol. 1998; 513: 889-894Crossref PubMed Scopus (281) Google Scholar, 7Pedersen BK Fischer CP Physiological roles of muscle-derived interleukin-6 in response to exercise.Curr Opin Clin Nutr Metab Care. 2007; 10: 265-271Crossref PubMed Scopus (152) Google Scholar In the study by Sabit et al,1Sabit R Thomas P Shale DJ Collins P Linnane SJ The effects of hypoxia on markers of coagulation and systemic inflammation in patients with COPD.Chest. 2010; 138: 47-51Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar subjects in the group with hypoxia experienced a hypoxic challenge with a mean oxygen saturation decline from 94% ± 2% to 90% ± 3%. When the oxygen concentration in the arterial blood fell, the chemoreceptors were stimulated and the ventilation increased, as shown by a rising respiratory rate (RR) or tidal volume.8Guyton AC Hall JE Textbook of Medical Physiology. 11th ed. Saunders, Philadelphia, PA2006: 518-520Google Scholar The muscle must be loaded with additional respiratory work, possibly contributing to a surge of IL-6. Although ventilation was not measured, the findings of higher RR and heart rate (HR) in the subjects receiving the hypoxic challenge were also in part compatible with our concern. (In the group with hypoxia, the RR increased from 14 ± 1 per min to 16 ± 3 per min, and the HR increased from 86 ± 6 per min to 94 ± 4 per min; in the control group, the RR increased from 14 ± 1 per min to 15 ± 1 per min, and the HR increased from 82 ± 4 per min to 87 ± 6 per min). In this study, the role of muscle-derived IL-6 should be further clarified in order to accurately document the effect of hypoxia on IL-6. Elevation of IL-6 Solely Is Not Sufficient to Infer Systemic Inflammation: ResponseCHESTVol. 139Issue 1PreviewWe thank Drs Su and Chou for their interest in our recent article in CHEST (July 2010),1 and submit our response to the comments made. We would like to clarify that although our study did demonstrate a rise in markers of coagulation and serum IL-6 in response to hypoxic challenge, such an association does not necessarily imply a causal relationship. We accept that the origin for the rise in serum IL-6 in response to hypoxia is not clear and, moreover, may not necessarily reflect a rise in IL-6 at the tissue level. Full-Text PDF