Smoking induces overexpression of immediate early genes in active Graves' ophthalmopathy.

Background: Cigarette smoking is a risk factor for the development of Graves' ophthalmopathy (GO). In a previous study of gene expression in intraorbital fat, adipocyte-related immediate early genes (IEGs) were overexpressed in patients with GO compared to controls. We investigated whether IEGs are upregulated by smoking and examined other pathways that may be affected by smoking. Methods: Gene expression in intraorbital fat was studied in smokers (n=8) and non-smokers (n=8) with severe active GO as well as in subcutaneous fat in thyroid-healthy smokers (n=5) and non-smokers (n=5) using microarray and real-time PCR. Results: With microarray, eight IEGs were upregulated more than 1.5-fold in smokers compared to non-smokers with GO. Five were chosen for confirmation and were also overexpressed with real-time PCR. Interleukin-1 beta /IL-1B/ (2.3-fold) and interleukin-6 /IL-6/ (2.4-fold) were upregulated both with microarray and with real-time PCR in smokers with GO compared to non-smokers. Major histocompatibility complex, class II, DR beta 1 /HLA-DRB1/ was upregulated with microarray (2.1-fold) and with borderline significance with real-time PCR. None of these genes were upregulated in smokers compared to non-smokers in subcutaneous fat. Conclusions: IEGs, IL-1B, and IL-6 were overexpressed in smokers with severe active GO compared to non-smokers suggesting that smoking activates pathways associated with adipogenesis and inflammation. This study underlines the importance of IEGs in the pathogenesis of GO and provides evidence for possible novel therapeutic interventions in GO. The mechanisms activated by smoking may be shared with other conditions such as rheumatoid arthritis.