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  • Title: Tumor necrosis factor-alpha regulation of thyroid transcription factor-1 and Pax-8 in rat thyroid FRTL-5 cells.
    Author: Ohmori M, Harii N, Endo T, Onaya T.
    Journal: Endocrinology; 1999 Oct; 140(10):4651-8. PubMed ID: 10499522.
    Abstract:
    Tumor necrosis factor-alpha (TNF-alpha) is known to modulate the expression of thyroid-specific genes, such as thyroglobulin (TG), contributing to the pathogenesis of autoimmune thyroid disease. In the present study, we show that TNF-alpha suppresses DNA-binding activity of thyroid transcription factors, Pax-8 and thyroid transcription factor-1 (TTF-1), which is, in part, involved in TNF-alpha-induced decrease in TG gene expression. Transfected into rat thyroid FRTL-5 cells, the activity of reporter plasmid containing the rat TG promoter ligated to a luciferase gene was significantly suppressed in the presence of TNF-alpha. In gel mobility shift analyses, protein-DNA complexes formed by TTF-1 and Pax-8 were reduced when the nuclear extracts prepared from TNF-alpha-treated FRTL-5 cells were used. The suppressive effect of TNF-alpha on TTF-1-DNA complex formation is, in part, caused by suppression of TTF-1 gene transcription by TNF-alpha. Expressions of TTF-1 messenger RNA and protein, which were assessed by Northern blot and Western blot analyses, respectively, were decreased by TNF-alpha treatment of FRTL-5 cells. In contrast, TNF-alpha did not affect the expression of Pax-8 messenger RNA. Treatment of FRTL-5 cells with TNF-alpha caused a decrease in Pax-8 protein in nuclear extracts and accumulation of the protein in the cytoplasm, as assessed by Western blot analyses. Mutation of the TTF-1/Pax-8-binding site lost the TNF-alpha-induced decrease in TG promoter activity in a transfection experiment. These results indicate that TNF-alpha suppresses the activity of TTF-1 and Pax-8 by different mechanisms, which, in part, seem to be involved in TNF-alpha-induced decrease in TG gene expression.
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