Role of antiapoptotic genes in genetic control of programmed cell death in Hashimoto's thyroiditis

Abstract Background In Hashimoto's thyroiditis (HT) thyroid cells die by apoptosis, programmed cell death. In addition to the reported abnormal Fas expression on thyrocytes, a decreased expression of the Bcl-2 antiapoptotic genes has also been demonstrated in thyrocytes. The ratio of the expression of death antagonists (e.g. Bcl-2 and Bcl-Xl) to death agonists (Bax, Bak, Bcl-Xs and Bad) appears to determine the survival or death of thyrocytes under both physiological and pathological conditions. Methods The constitutive expression of Bcl-X was investigated in thyroid cells from ten multinodular goitre (MNG), ten Graves disease and four HT samples by immunofluorescence, confocal microscopy and Western blotting. The effect of proinflammatory cytokines (interferon (IFN) γ, tumour necrosis factor (TNF) α and interleukin (IL) 1 on Bcl-X expression on cultured thyrocytes was also studied. Results By in situ staining, an overall decreased Bcl-X expression was observed within the thyrocyte compartment in HT samples in comparison to that seen on thyrocytes from ten samples of MNG thyroid. Intrathyroidal lymphocytes were positive for Bcl-X. These findings were quantified using confocal microscopy which demonstrated an intensity of Bcl-X staining in MNG twice that of HT specimens. The ten specimens of Graves disease showed an intermediate and patchy staining on thyrocytes. In vitro studies have confirmed constitutive Bcl-X expression both by flow cytometry and Western blotting analysis with the latter showing a 27-kDa signal in all samples that corresponds to Bcl-Xl. IFN-γ, alone and in combination with TNF-α and IL-I, decreased Bcl-X expression on thyrocytes. Conclusion HT thyrocytes underexpress Bcl-X whereas intrathyroidal lymphocytes have been found to be positive. It is proposed that the decreased Bcl-X expression on thyrocytes of HT glands occurs as a result of proinflammatory cytokine release by infiltrating activated lymphocytes. The overall impairment of antiapoptotic gene protection may contribute to the susceptibility of HT thyrocytes to apoptosis.