The role of interferon-gamma in lymphocytic thyroiditis: its functional and pathological effect on human thyrocytes in culture

Abstract

SUMMARYInterferon-gamma (IFN-y) has been recognized to possess diverse non-immunological effects on epithelial cells such as cellular growth and differentiation. We have previously demonstrated that IFN-'/ suppressed thyroid-stimulating hormone (TSH)-stimulated thyroglobutin (TG) synthesis in human thyrocytes through inhibition of TG gene transcription. To define the pathological mechanism involved in the aetion of IFN-v. we studied the ultrastructural changes of human thyrocytes cultured in monolayer. Stimulation of the thyrocytes with TSH 10 mU/m! for 2 days resulted in marked increase in TG release into the medium. This was accompanied by elongation of microvilii. increa.se in follicles and acinar formation, increase in secretory granules and prominence of Golgi apparatus and rough-surfaced endoplasmic reticulum. Addition of IF-N-7(500 U/ml) resulted in marked degeneration with shrinkage of the cell membrane, vacuolation of cytoplasm, swollen mitochondria and presence of lysosomal granules. Co-culturing the thyrocytes with the IFN-y and TSH resulted in suppression of the morphological responsiveness to TSH. There was also suppression of TSH-induced TG secretion. However, at 500 U/ml IFN-"; did not cause lysis of the thyrocytes as estimated by the cellular DNA content. Furthermore, binucleated ceils were frequently encountered in those wells that were treated with IFN-y for either 2 or 5 days. The findings suggest that IFN-y resulted in dc-diffcrentiation and degeneration of the thyrocytes. which subsequently regained the growth potcniia! and showed attempts at regeneration. This may explain why most patients with lymphocytic thyroiditis recover from the aeute injury and do nol suffer from permanent hypothyroidism.

The molecular basis of the non-thyroidal illness syndrome

“…IFNg is a cytokine that is mainly involved in anti-viral and anti-bacterial responses and is produced by natural killer and T-cells. INFg has a variety of effects on human thyrocytes in culture; it inhibits TSH-induced TH and Tg secretion (Nagayama et al 1987, Kung et al 1992 as well as Tg mRNA expression (Sato et al 1990), TSH-induced TPO expression ) and the TSH-and cAMPinduced upregulation of TSH receptors on the thyrocyte (Nishikawa et al 1993). IFNg also inhibits the TSH-induced increase in NIS expression in rat FTRL-5 cells resulting in diminished iodide uptake (Ajjan et al 1998).…”

Iodide, cytokines and TSH-receptor expression in Graves' disease

“…In addition to immunological parameters. ¡FN-gamma also affects functional thyroid parameters, decreasing thyroid peroxidase (TPO) (Ashizawa et al, 1989), thyroglobulin (TG) (Kung et al. 1992) and TSH-R (Nishikawa et al, 1993) gene expression, at least in part, by reducing thyroid transcription factor-I binding to its recognition site at the respective promotor regions (Ohe et al, 1996).…”

Pentoxifylline Explores New Horizons in Treatment of Hashimoto Thyroiditis

“…Genetic development of HT is related to genes that over-express Interferon gamma (IFN-γ) [11]. As the disease initiates, thyrocytes enter a cytostatic state followed by progressive destruction and impaired regeneration of thyroid gland which could result in hypothyroidism [12].…”