Dear Sir,
Increased generation of reactive oxygen species (ROS) is thought to play a role in the pathogenesis of Graves' ophthalmopathy (GO) [1,2]. Selenium (Se) is an antioxidant agent that has been recently shown to improve significantly the course of mild GO [2]. There is good evidence that oxidative stress plays a role in GO: orbital fibroblasts of GO patients have higher contents of malondialdehyde, superoxide anions and hydrogen peroxide than control orbital fibroblasts [3]. Orbital fibroblasts are recognized as the prime target cells of the autoimmune attack in GO [3].
We suggest a possible interplay between nuclear factor-κB (NF-κB), pro-inflammatory cytokines (which activate and are activated by NF-κB, by amplifying and perpetuating orbital inflammation), ROS, Se and glucocorticoids (GC) (fig. 1) in GO [4,5]. Many of the GC effects are mediated through an inhibition of NF-κB [6] (fig. 1). GC binding to its receptor may have a dual effect on gene activation such as activation of transcription (transactivation) or a suppression of transcription (transrepression) by interacting with NF-κB; consequently, the production of anti-inflammatory proteins is increased (transactivation), whereas the inflammatory ones are diminished (transrepression) [7].
In our view, the decreased efficacy of GC therapy in current smokers [8] might be explained - at least in part - by the antagonism GC - ROS revealed at the NF-κB level [4] (fig. 1). Cigarette smoking is a major source of ROS which are able to stimulate the NF-κB pathway (fig. 1), a cornerstone of immune and inflammatory response [5].
Future studies (immunosuppressive therapy plus Se) in patients with more severe GO are, at least in part, justified by the following data: (a) GC [6,7] and Se [9] seem to have a similar inhibitory (possibly synergistic) effect on NF-κB activity (fig. 1), and (b) opposite effects on the NF-κB pathway of current smoking (stimulatory effect via a prooxidant effect) [5] and Se (inhibitory effect via an antioxidant action) [9] (fig. 1). Therefore, a detailed analysis of the influence of smoking upon any antioxidant therapy in patients with GO would be valuable.
Disclosure Statement
The authors have no conflicts of interest to disclose.
Footnotes
verified
References
- 2↑
Marcocci C, Kahaly GJ, Krassas GE, Bartalena L, Prummel M, Stahl M, Altea MA, Nardi M, Pitz S, Boboridis K, Sivelli P, von Arx G, Mourits MP, Baldeschi L, Bencivelli W, Wiersinga WM: Selenium and the course of mild Graves' ophthalmopathy. N Engl J Med 2011;364:1920-1931.
- 3↑
Wiersinga WM: Autoimmunity in Graves' ophthalmopathy: the result of an unfortunate marriage between TSH receptors and IGF-1 receptors? J Clin Endocrinol Metab 2011;96:2386-2394.
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Ursu H, Badiu C, Gheorghiu ML: Selenium, mild Graves' ophthalmopathy and current smoking status. Acta Endocrinol (Buc) 2012;8:467-470.
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Barnes PJ, Karin M: Nuclear factor-κB - a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997;336:1066-1071.
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Krassas GE, Heufelder AE: Immunosuppressive therapy in patients with thyroid disease: an overview of current concepts. Eur J Endocrinol 2001;144:311-318.
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Zang S, Ponto KA, Kahaly GJ: Intravenous glucocorticoids for Graves' orbitopathy: efficacy and morbidity. J Clin Endocrinol Metab 2011;96:320-332.
- 8↑
Bartalena L, Marcocci C, Tanda ML, Manetti L, Dell'Unto E, Bartolomei MP, Nardi M, Martino E, Pinchera A: Cigarette smoking and treatment outcomes in Graves' ophthalmopathy. Ann Intern Med 1998;129:632-635.
- 9↑
Maehira F, Miyagi I, Eguchi Y: Selenium regulates transcription factor NF-κB activation during the acute phase reaction. Clin Chim Acta 2003;334:163-171.