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Activation of Transcriptionally Active Nuclear Factor-B by Tumor Necrosis Factor- and Its Inhibition by Antioxidants in Rat Thyroid FRTL-5 Cells¹

Department of Endocrinology and Metabolism, Division of Molecular and Cellular Adaptation, Research Institute of Environmental Medicine (T.K., F.K., T.N., H.S.), Nagoya University, Nagoya 464–01; and Department of Surgery II, Nagoya University School of Medicine (T.K., T.I., H.F.), Nagoya 466, Japan

Address all correspondence and requests for reprints to: Fukushi Kambe, Department of Endocrinology and Metabolism, Division of Molecular and Cellular Adaptation, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464–01, Japan. E-mail: kambe{at}riem.nagoya-u.ac.jp

Tumor necrosis factor- (TNF-) exerts pleiotropic effects on thyroid follicular cells. However, the intracellular signaling pathway for the TNF- action has not been well elucidated. The present study examined the effects of TNF- on the activation of nuclear factor- B (NF-B) and on the expression of interleukin (IL)-6 gene in rat thyroid FRTL-5 cells. The treatment of the cells with TNF- resulted in the nuclear translocation of p65-p50 heterodimer as well as p50-p50 homodimer NF-Bs. The treatment with the antioxidants 20 mM N-acetyl-L-cysteine (NAC) and 10 µM pyrrolidine dithiocarbamate (PDTC) inhibited the TNF--dependent activation of p65-p50 heterodimer but not the p50-p50 homodimer, indicating that generation of oxidants is required for the activation of the heterodimer NF-B. When the plasmid containing the multimerized NF-B sites upstream of a luciferase reporter gene was transfected into FRTL-5 cells, the treatment with NAC or PDTC prevented the TNF--dependent increase in the luciferase activities, indicating that the p65-p50 heterodimer is a transcriptionally active NF-B. Accordingly, the TNF--dependent increase in IL-6 messenger RNA and in secretion of the protein was prevented by the treatment with NAC. These results strongly suggest that TNF- increases the IL-6 gene expression through the activation of NF-B in the thyroid cells, and that antioxidants suppress the TNF--dependent IL-6 expression by inhibiting the activation of the transcriptionally active NF-B.

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