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Communications to the Editor |

Interleukin-6, Obstructive Sleep Apnea, and Obesity FREE TO VIEW

Ken-ichiro Inoue; Hirohisa Takano; Toshikazu Yoshikawa
Author and Funding Information

Affiliations: Kyoto Prefectural University of Medicine, Kyoto, Japan,  Institute of Respiratory Diseases, University of Bari, Bari, Italy,  Imperial College School of Medicine, National Heart Lung Institute, London, UK

Correspondence to: Ken-ichiro Inoue, MD, Department of Internal Medicine, Naka Central Hospital, 1733-1, Iida, Naka-cho, Naka-gun 311-0134, Japan; e-mail: keni@kk.iij4u.or.jp



Chest. 2003;124(4):1621-1623. doi:10.1378/chest.124.4.1621-a
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To the Editor:

Carpagnano and colleagues1 recently reported in CHEST (October 2002) a significant increase in 8-isoprostane and interleukin (IL)-6 levels in the exhaled breath condensate of obstructive sleep apnea (OSA) patients compared with that of obese subjects. In the article, they referred to a close correlation between IL-6 levels and obesity, stating “The higher concentration of this cytokine in obese subjects compared to control subjects…. ” Apart from the increased concentration of this cytokine, its function in obesity is complicated. IL-6 is expressed not only in adipose tissues,3 but also in neurons of hypothalamic nuclei, which regulate body composition,45 as well as in nonneurons such as astrocytes, microglia, and brain endothelial cells.6 A recent study by Wallenius and coworkers7 demonstrated that IL-6 knockout mice developed mature-onset obesity. The obesity was concomitant with decreased glucose tolerance and increased circulatory triglyceride levels in females, as well as increased leptin levels and leptin insensitivity in older mice of both genders. Interestingly, intracerebroventricular IL-6 injection, but not intraperitoneal IL-6 injection, increased energy expenditure, suggesting that centrally acting IL-6 exerts antiobesity effects.

Numerous studies have documented the opposite roles of IL-6 in inflammatory models. For example, IL-6 plays proinflammatory roles in carrageenan-induced pleuritis8 and chronic arthritis,9 but plays anti-inflammatory roles in cerulein-induced pancreatitis10 and endotoxemia.11 These experiments demonstrate that this vital cytokine can provide a useful approach in the treatment of various diseases. In conclusion, further experimental and clinical studies are needed to establish the roles of IL-6 in OSA syndrome as well as obesity, not only as a diagnostic tool, but also as a therapeutic target.

Carpagnano, GE, Kharitonov, SA, Resta, O, et al (2002) Increased 8-isoprostane and interleukin-6 in breath condensate of obstructive sleep apnea patients.Chest122,1162-1167. [CrossRef]
 
Mohamed-Ali, V, Goodrick, S, Rawesh, A, et al Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha,in vivo.J Clin Endocrinol Metab1997;82,4196-4200
 
Fried, SK, Bunkin, DA, Greenberg, AS Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.J Clin Endocrinol Metab1998;83,847-850
 
Schobitz, B, de Kloet, ER, Sutanto, W, et al Cellular localization of interleukin 6 mRNA and interleukin 6 receptor mRNA in rat brain.Eur J Neurosci1993;5,1426-1435. [CrossRef]
 
Shizuya, K, Komori, T, Fujiwara, R, et al The expression of mRNAs for interleukin-6 (IL-6) and the IL-6 receptor (IL-6R) in the rat hypothalamus and midbrain during restraint stress.Life Sci1998;62,2315-2320. [CrossRef]
 
Aschner, M Immune and inflammatory responses in the CNS: modulation by astrocytes.Toxicol Lett1998;102,283-287
 
Wallenius, V, Wallenius, K, Ahren, B, et al Interleukin-6-deficient mice develop mature-onset obesity.Nat Med2002;8,75-79. [CrossRef]
 
Cuzzocrea, S, Sautebin, L, De Sarro, G, et al Role of IL-6 in the pleurisy and lung injury caused by carrageenan.J Immunol1999;163,5094-5104
 
Alonzi, T, Fattori, E, Lazzaro, D, et al Interleukin 6 is required for the development of collagen-induced arthritis.J Exp Med1998;187,461-468. [CrossRef]
 
Cuzzocrea, S, Mazzon, E, Dugo, L, et al Absence of endogenous interleukin-6 enhances the inflammatory response during acute pancreatitis induced by cerelein in mice.Cytokine2002;18,274-285. [CrossRef]
 
Xing, Z, Gauldie, J, Cox, G, et al IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses.J Clin Invest1998;101,311-320. [CrossRef]
 
To the Editor:

We thank Inoue and colleagues for raising comments on our recent study in which we described a significant increase of 8-isoprostane and interleukin (IL)-6 in the exhaled breath condensate of patients with obstructive sleep apnea (OSA) and obese subjects. In his letter, Dr. Inoue underlined the importance of improving our understanding of IL-6 in OSA as well as in obesity.

IL-6 has recently aroused a lot of interest in the study of inflammation in several respiratory diseases. However, this cytokine seems to have contradictory roles, as it mediates both proinflammatory and anti-inflammatory actions.1 IL-6 is involved in the resolution of acute and chronic inflammation, via the induction of glucocorticoid release, as well as via the induction of antagonists of IL-1β and tumor necrosis factor-α. At the same time, this cytokine regulates production of acute phase proteins, which may locally limit the actions of inflammatory cells.2

IL-6 has been implicated in the pathogenesis of obesity and OSA.34 Its involvement in these clinical conditions was supposed by Vgontzas et al,5 who identified higher concentrations of IL-6 in the blood of patients with OSA and obesity, and our recent study4 demonstrated increased concentrations of this cytokine in their airway.

On the basis of our findings, we suggest that measuring exhaled concentrations of IL-6 may be useful in screening obese subjects at high risk of acquiring OSA, as well as in monitoring of progression and response to treatment.4 However, prospective studies are needed to evaluate the clinical value of this measurement. We agree with Dr. Inoue that additional studies are necessary to better clarify the role of IL-6 and to determine whether it is a useful measurement in the diagnosis and treatment of OSA.

References
Carpagnano, GE, Barnes, PJ, Geddes, DM, et al Increased leukotriene B4and interleukin-6 in exhaled breath condensate in cystic fibrosis.Am J Respir Crit Care Med2003;167,1109-1112. [CrossRef]
 
Tilg, H, Dinarello, CA, Mier, JW IL-6 and APPs: anti-inflammatory and immunosuppressive mediators.Immunol Today1997;18,428-432. [CrossRef]
 
Vgontzas, AN, Papanicolaou, DA, Bixler, EO, et al Circadian interleukin-6 secretion and quantity and depth of sleep.J Clin Endocrinol Metab1999;84,2603-2607. [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]
 
Vgontzas, AN, Papanicolaou, DA, Bixler, EO, et al Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity.Clin Endocrinol Metab1997;82,1313-1316. [CrossRef]
 

Figures

Tables

References

Carpagnano, GE, Kharitonov, SA, Resta, O, et al (2002) Increased 8-isoprostane and interleukin-6 in breath condensate of obstructive sleep apnea patients.Chest122,1162-1167. [CrossRef]
 
Mohamed-Ali, V, Goodrick, S, Rawesh, A, et al Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha,in vivo.J Clin Endocrinol Metab1997;82,4196-4200
 
Fried, SK, Bunkin, DA, Greenberg, AS Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.J Clin Endocrinol Metab1998;83,847-850
 
Schobitz, B, de Kloet, ER, Sutanto, W, et al Cellular localization of interleukin 6 mRNA and interleukin 6 receptor mRNA in rat brain.Eur J Neurosci1993;5,1426-1435. [CrossRef]
 
Shizuya, K, Komori, T, Fujiwara, R, et al The expression of mRNAs for interleukin-6 (IL-6) and the IL-6 receptor (IL-6R) in the rat hypothalamus and midbrain during restraint stress.Life Sci1998;62,2315-2320. [CrossRef]
 
Aschner, M Immune and inflammatory responses in the CNS: modulation by astrocytes.Toxicol Lett1998;102,283-287
 
Wallenius, V, Wallenius, K, Ahren, B, et al Interleukin-6-deficient mice develop mature-onset obesity.Nat Med2002;8,75-79. [CrossRef]
 
Cuzzocrea, S, Sautebin, L, De Sarro, G, et al Role of IL-6 in the pleurisy and lung injury caused by carrageenan.J Immunol1999;163,5094-5104
 
Alonzi, T, Fattori, E, Lazzaro, D, et al Interleukin 6 is required for the development of collagen-induced arthritis.J Exp Med1998;187,461-468. [CrossRef]
 
Cuzzocrea, S, Mazzon, E, Dugo, L, et al Absence of endogenous interleukin-6 enhances the inflammatory response during acute pancreatitis induced by cerelein in mice.Cytokine2002;18,274-285. [CrossRef]
 
Xing, Z, Gauldie, J, Cox, G, et al IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses.J Clin Invest1998;101,311-320. [CrossRef]
 
Carpagnano, GE, Barnes, PJ, Geddes, DM, et al Increased leukotriene B4and interleukin-6 in exhaled breath condensate in cystic fibrosis.Am J Respir Crit Care Med2003;167,1109-1112. [CrossRef]
 
Tilg, H, Dinarello, CA, Mier, JW IL-6 and APPs: anti-inflammatory and immunosuppressive mediators.Immunol Today1997;18,428-432. [CrossRef]
 
Vgontzas, AN, Papanicolaou, DA, Bixler, EO, et al Circadian interleukin-6 secretion and quantity and depth of sleep.J Clin Endocrinol Metab1999;84,2603-2607. [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]
 
Vgontzas, AN, Papanicolaou, DA, Bixler, EO, et al Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity.Clin Endocrinol Metab1997;82,1313-1316. [CrossRef]
 
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