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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. ​(fig.1)1) in GO [4,5]. Many of the GC effects are mediated through an inhibition of NF-κB [6] (fig. ​(fig.1).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].    Fig. 1  Positive regulatory loop of pro-inflammatory cytokines (IL-1 = interleukin-1, TNF-α = tumor necrosis factor-α) and NF-κB regulated by GC, Se and ROS in GO. Cigarette smoking is a major source of ROS.    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. ​(fig.1).1). Cigarette smoking is a major source of ROS which are able to stimulate the NF-κB pathway (fig. ​(fig.1),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. ​(fig.1),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. ​(fig.1).1). Therefore, a detailed analysis of the influence of smoking upon any antioxidant therapy in patients with GO would be valuable.

Oxidative Stress, Nuclear Factor-κB Pathway and Current Smoking in Graves' Ophthalmopathy