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Communications to the Editor |

Increased Plasma Interleukin-6 Is Associated With the Pathogenesis of Obstructive Sleep Apnea SyndromeIncreased Plasma Interleukin-6 Is Associated With the Pathogenesis of Obstructive Sleep Apnea Syndrome FREE TO VIEW

Shinji Teramoto, MD, FCCP; Hiroshi Yamamoto, MD; Yasuyoshi Ouchi, MD
Author and Funding Information

Affiliations: The University of Tokyo Hospital, Tokyo, Japan,  Kyoto Prefectural University of Medicine, Kyoto, Japan

Correspondence to: Shinji Teramoto, MD, FCCP, Department of Geriatric Medicine, University of Tokyo Hospital, 7-3-1 Hongo Bunkyo-ku, Tokyo, Japan 113-8655 Japan; e-mail: shinjit-tky@umin.ac.jp



Chest. 2004;125(5):1964-1965. doi:10.1378/chest.125.5.1964
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Published online

To the Editor:

In a recent issue of CHEST, Inoue and colleagues (October 2003)1disagreed with the results of a study by Carpagnano and colleagues2 regarding the role of interleukin (IL)-6 in the pathogenesis of obesity and obstructive sleep apnea syndrome (OSAS). In 2002, Carpagnano and colleagues2 reported that the measurement of IL-6 and 8-isoprostane levels, which indicate inflammation and oxidative stress in the airways of OSAS patients, may prove to be useful in screening and monitoring obese patients who have a high risk of developing OSAS. However, Inoue and colleagues1 suggested that further experimental and clinical studies are needed to establish the role of IL-6 in OSAS as well as obesity, not only as a diagnostic tool, but also as a therapeutic target. We basically agree with the authors that IL-6 affects the pathogenesis of obesity, obstructive sleep apnea, and metabolic disease. The proinflammatory cytokines may not always be the only specific cause of the pathogenesis of sleep apnea. However, some clinical data strongly indicate that IL-6 levels are elevated in patients with OSAS, but not in obese subjects.36 In our data, the mean (± SD) plasma level of IL-6 is greater in OSAS patients (7.3 ± 1.0 ng/mL) than in obese patients without OSAS (3.4 ± 0.6 ng/mL).3More importantly, we and other investigators have reported that the increased levels of IL-6 in patients with OSAS significantly decreases after treatment with nasal continuous positive airway pressure (nCPAP) [Table 1]. It indicates that obstructive sleep apnea itself contributes to the increased levels of proinflammatory cytokines and systemic inflammation. Interestingly, the spontaneous production of IL-6 by monocytes isolated from patients with OSAS is also elevated and is decreased by nCPAP therapy.4 This evidence may explain in part the increased concentrations of proinflammatory cytokines, including IL-6, in the airways of OSAS patients. Furthermore, the plasma levels of tumor necrosis factor (TNF)-α) and high-sensitivity C-reactive protein (hsCRP) are also elevated in patients with OSAS. IL-6 and hsCRP levels were independently associated with OSAS severity, as indicated by the apnea-hypopnea index. Furthermore, the plasma levels of IL-6 and TNF-α are associated with the levels of hsCRP, suggesting that increased numbers of proinflammatory cytokines are involved in that mechanism causing elevated levels of hsCRP in these patients. These data support the notion that inflammatory processes are activated in atherosclerotic lesions in patients with OSAS. Although hsCRP is a good marker of cardiovascular complication,7 other inflammatory mediators also are involved in atherosclerosis. In addition, the antagonism of IL-6 improves the endothelial function, suggesting that CRP and IL-6 synergistically affect endothelial dysfunction. Conceivably, hsCRP and other inflammatory cytokines accelerate the progression of atherosclerosis in patients with OSAS.

Because nCPAP treatment could reduce the levels of IL-6, TNF, and hsCRP in OSAS patients, nCPAP therapy may beneficially suppress the systemic inflammation and metabolic syndrome in OSAS, possibly resulting in the deccrelation of atherosclerotic lesions in OSAS patients.810

This study was supported by an Evidence-Based Medicine research grant from the Ministry of Health and Welfare, and by a research grant from the Japan Arteriosclerosis Prevention Fund.

Table Graphic Jump Location
Table 1. Proinflammatory Markers in Obesity With/Without OSAS*
* 

Values given as mean ± SD unless otherwise indicated. CPAP(−) = without CPAP therapy; CPAP(+) = with CPAP therapy.

 

p < 0.05 compared with the same value of obese controls subjects.

 

p < 0.05 compared with the same value before CPAP.

Inoue, K, Takano, H, Yoshikawa, T (2003) Interleukin-6, obstructive sleep apnea, and obesity.Chest124,1621-1623. [CrossRef]
 
Carpagnano, GE, Kharitonov, SA, Resta, O, et al Increased 8-isoprostane and interleukin-6 in breath condensate of obstructive sleep apnea patients.Chest2002;122,1162-1167. [CrossRef] [PubMed]
 
Teramoto, S, Yamamoto, H, Ouchi, Y Increased C-reactive protein and increased plasma interleukin-6 may synergistically affect the progression of coronary atherosclerosis in obstructive sleep apnea syndrome [letter].Circulation2003;107,E40-0. [CrossRef] [PubMed]
 
Yokoe, T, Minoguchi, K, Matsuo, H, et al Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure.Circulation2003;107,1129-1134. [CrossRef] [PubMed]
 
Shamsuzzaman, AS, Winnicki, M, Lanfranchi, P, et al Elevated C-reactive protein in patients with obstructive sleep apnea.Circulation2002;105,2462-2464. [CrossRef] [PubMed]
 
Vgontzas, AN, Papanicolaou, DA, Bixler, EO, et al Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia.J Clin Endocrinol Metab2000;85,1151-1158. [CrossRef] [PubMed]
 
Cusack, MR, Marber, MS, Lambiase, PD, et al Systemic inflammation in unstable angina is the result of myocardial necrosis.J Am Coll Cardiol2002;39,1917-1923. [CrossRef] [PubMed]
 
Teramoto, S, Kume, H, Matsuse, T Ambulatory blood pressure after sleep apnoea treatment [letter]. Lancet. 2002;;360 ,.:341
 
Teramoto, S, Kume, H, Matsuse, T, et al Oxygen administration improves the serum level of nitric oxide metabolites in patients with obstructive sleep apnea syndrome.Sleep Med2003;4,403-407. [CrossRef] [PubMed]
 
Teramoto, S, Kume, H, Matsuse, T, et al The risk of future cardiovascular diseases in the patients with OSAS is dependently or independently associated with obstructive sleep apnoea.Eur Respir J2001;17,573-574. [CrossRef] [PubMed]
 

Increased Plasma Interleukin-6 Is Associated With the Pathogenesis of Obstructive Sleep Apnea Syndrome

To the Editor:

We appreciate the proper comment on our letter and the excellent data by Teramoto et al. After seeing their Table 1 , we do not have any questions about interleukin (IL)-6 as a screening and monitoring option in obstructive sleep apnea syndrome. In the published letter, we would have liked to emphasize the doubt about the therapeutic value of IL-6, especially in obesity. Apart from other inflammatory diseases such as sepsis, bronchial asthma, and rheumatoid arthritis, systemic and/or local expression of IL-6 does not always indicate that the cytokine can be expected to become the therapeutic target in obesity. An experimental study1using IL-6 gene knock-out mice suggested that IL-6 may be an “antiobesity” molecule. Also, Febbraio and Pedersen2referred to the possibility of IL-6 as a drug for obesity. However, another group3 suggested a role of IL-6 in central obesity, insulin resistance, and atherosclerosis.

References
Wallenius, V, Wallenius, K, Ahren, B, et al Interleukin-6-deficient mice develop mature-onset obesity.Nat Med2002;8,75-79. [CrossRef] [PubMed]
 
Febbraio, MA, Pedersen, BK Muscle-derived interleukin-6: mechanisms for activation and possible biological roles.FASEB J2002;16,1335-1347. [CrossRef] [PubMed]
 
Yudkin, JS, Kumari, M, Humphries, SE, et al Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?Atherosclerosis2000;148,209-214. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1. Proinflammatory Markers in Obesity With/Without OSAS*
* 

Values given as mean ± SD unless otherwise indicated. CPAP(−) = without CPAP therapy; CPAP(+) = with CPAP therapy.

 

p < 0.05 compared with the same value of obese controls subjects.

 

p < 0.05 compared with the same value before CPAP.

References

Inoue, K, Takano, H, Yoshikawa, T (2003) Interleukin-6, obstructive sleep apnea, and obesity.Chest124,1621-1623. [CrossRef]
 
Carpagnano, GE, Kharitonov, SA, Resta, O, et al Increased 8-isoprostane and interleukin-6 in breath condensate of obstructive sleep apnea patients.Chest2002;122,1162-1167. [CrossRef] [PubMed]
 
Teramoto, S, Yamamoto, H, Ouchi, Y Increased C-reactive protein and increased plasma interleukin-6 may synergistically affect the progression of coronary atherosclerosis in obstructive sleep apnea syndrome [letter].Circulation2003;107,E40-0. [CrossRef] [PubMed]
 
Yokoe, T, Minoguchi, K, Matsuo, H, et al Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure.Circulation2003;107,1129-1134. [CrossRef] [PubMed]
 
Shamsuzzaman, AS, Winnicki, M, Lanfranchi, P, et al Elevated C-reactive protein in patients with obstructive sleep apnea.Circulation2002;105,2462-2464. [CrossRef] [PubMed]
 
Vgontzas, AN, Papanicolaou, DA, Bixler, EO, et al Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia.J Clin Endocrinol Metab2000;85,1151-1158. [CrossRef] [PubMed]
 
Cusack, MR, Marber, MS, Lambiase, PD, et al Systemic inflammation in unstable angina is the result of myocardial necrosis.J Am Coll Cardiol2002;39,1917-1923. [CrossRef] [PubMed]
 
Teramoto, S, Kume, H, Matsuse, T Ambulatory blood pressure after sleep apnoea treatment [letter]. Lancet. 2002;;360 ,.:341
 
Teramoto, S, Kume, H, Matsuse, T, et al Oxygen administration improves the serum level of nitric oxide metabolites in patients with obstructive sleep apnea syndrome.Sleep Med2003;4,403-407. [CrossRef] [PubMed]
 
Teramoto, S, Kume, H, Matsuse, T, et al The risk of future cardiovascular diseases in the patients with OSAS is dependently or independently associated with obstructive sleep apnoea.Eur Respir J2001;17,573-574. [CrossRef] [PubMed]
 
Wallenius, V, Wallenius, K, Ahren, B, et al Interleukin-6-deficient mice develop mature-onset obesity.Nat Med2002;8,75-79. [CrossRef] [PubMed]
 
Febbraio, MA, Pedersen, BK Muscle-derived interleukin-6: mechanisms for activation and possible biological roles.FASEB J2002;16,1335-1347. [CrossRef] [PubMed]
 
Yudkin, JS, Kumari, M, Humphries, SE, et al Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?Atherosclerosis2000;148,209-214. [CrossRef] [PubMed]
 
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