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Tumor Necrosis Factor- and Interferon- Suppress Both Gene Expression and Deoxyribonucleic Acid-Binding of TTF-2 in FRTL-5 Cells

Third Department of Internal Medicine, Yamanashi Medical University, Tamaho, Yamanashi 409-3898, Japan

Address all correspondence and requests for reprints to: Toshimasa Onaya M.D., Ph.D., Third Department of Internal Medicine, Yamanashi Medical University, Tamaho, Yamanashi 409-3898, Japan. E-mail: onayat{at}res.yamanashi-med.ac.jp

Tumor necrosis factor- (TNF-) and interferon- (IFN-) are cytokines that can individually or additively suppress thyroid cell function and the expression of thyroid-specific genes, such as thyroglobulin (TG) and thyroperoxidase (TPO). Thyroid transcription factor-2 (TTF-2) is a DNA-binding protein that modulates the expression of TG and TPO genes. In the present study, we examine the effects of TNF- and IFN- on TTF-2 gene expression, as well as the DNA-binding activity of TTF-2. FRTL-5 cells were maintained in 5H medium containing 0.2% calf serum for 7 days, then incubated with TNF-, IFN-, or TNF- plus IFN-. Total RNA was isolated and Northern blotted. TNF- (50 ng/ml) only slightly suppressed (61 ± 2% compared with control), whereas IFN- (100 U/ml) modestly decreased TTF-2 messenger RNA (mRNA) levels (34 ± 4%). TNF- and IFN- simultaneously caused a marked decrease in TTF-2 mRNA levels (13 ± 2%). The suppressive effects of TNF- and IFN- on TTF-2 mRNA levels were concentration dependent and maximal at 50 ng/ml TNF- with 100 U/ml IFN-. The suppressive effect was also time dependent, reaching a maximum 12 h after exposure. Moreover, the suppressive effects of TNF- and IFN- upon rat TG and TTF-2 mRNA levels were similar. To test whether TNF- and IFN- alter TTF-2-binding to DNA, we performed electrophoretic mobility shift assays using a TTF-2-binding element in the rat TG gene as a probe. Formation of the TTF-2/DNA complex was decreased by TNF- and/or IFN-. Our results demonstrate that TNF- and IFN- additively reduce the gene expression and DNA-binding of TTF-2. These data suggest that TTF-2 is involved in the TNF- and IFN--induced suppression of thyroid-specific gene expression.

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