INTERFERON-_yINHIBITS THYROTROPIN-INDUCED THYROIDAL PEROXIDASE GENE EXPRESSION IN CULTURED HUMAN THYROCYTES

Abstract

We have previously demonstrated that interferon-gamma (IFN-gamma) induced HLA-DR antigen and also inhibited thyrotropin (TSH)-induced triiodothyronine (T3) and thyroglobulin (Tg) secretion from cultured human thyrocytes. In order to further clarify the inhibitory effect of IFN-gamma on TSH-stimulated thyroid hormone secretion, we have examined human thyroid peroxidase (TPO) gene expression. Thyrocytes dispersed from Graves' thyroid tissues were incubated with TSH with or without IFN-gamma. Total RNA was extracted, separated and hybridized with 32P-labelled human TPO cDNA. Thyrocytes expressed four TPO mRNA transcripts (4.0, 3.2, 2.1 and 1.7kb, respectively), all of which were stimulated by TSH. IFN-gamma inhibited TSH-stimulated TPO mRNA in a dose dependent manner (0.01-10U/mL). 1 U/mL IFN-gamma caused maximal suppression of TSH-stimulated TPO mRNA levels to basal levels. IFN-gamma also inhibited 8-bromo-cyclic AMP-stimulated TPO mRNA levels. In contrast, the gamma-actin mRNA hybridization signal was not altered in control or treated cells. These results demonstrate that IFN-gamma directly inhibits TSH-stimulated TPO gene expression and provide further support for a role of IFN-gamma as a local modulator of thyroid hormone synthesis.

Role of cytokines in the pathogenesis of the euthyroid sick syndrome

“…IL-1a and IL-1b caused a dose-dependent decrease in thyroid peroxidase (TPO) mRNA levels in cultured human thyrocytes from patients with Graves' disease (51) ( Table 1). Similar results were obtained, using the same cell system, with IL-6 (52) and IFN-g (53). The latter cytokine also reduced the basal and TSHstimulated TPO content of cultured human thyrocytes (54).…”

Hypothyroidism in transgenic mice expressing IFN-γ in the thyroid

“…Over the past few years, the role of cytokines in regulating thyroid function has been the focus of several studies, which have shown, in general, that cytokines such as tumor necrosis factor ␣, IL-1␣, and IFN-␥ have an inhibitory effect on thyroid function (18). Focusing on IFN-␥, it has been shown, for example, that this cytokine inhibits thyrotropininduced transcription of TG (19), TPO (20), NIS (18), and TSH-R (21) genes, the last one mediated by a reduction of the binding of thyroid transcription factor-1 to the TSH-R promoter (22). All these studies have been performed in vitro, using either primary thyroid cell cultures or, more commonly, the rat thyroid cell line FRTL-5 and, thus, have looked at only the acute effects that the addition of IFN-␥ to the culture medium has on the thyroid cell.…”

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

“…While it inhibited thyroid hormone synthesis and thyroid peroxidase expression in thyrocytes [ 16], it induced morphological differentiation in neuroblastoma ceil lines with increase in eell-specific surface antigen expression and also inerease in cytoskeletal proteins [17]. Thus, IFN-7 can result in either differentiation or de-differentiation depending on the cell type studied [18].…”