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Endocrinology Vol. 139, No. 4 1715-1722
Copyright © 1998 by The Endocrine Society

ARTICLES

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

Toyone Kikumori, Fukushi Kambe, Takashi Nagaya, Tsuneo Imai, Hiroomi Funahashi and Hisao Seo

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




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