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Tumor Necrosis Factor- Attenuates Thyroid Hormone-Induced Apoptosis in Vascular Endothelial Cell Line XLgoo Established from Xenopus Tadpole Tails

Department of Biosciences (S.M., K.T.,S.O., S.T., T.S., N.T., M.I.), School of Science, Kitasato University, Sagamihara, Kanagawa 228-8555 Japan; and Division of Embryology and Genetics (Y.Y.), Institute for Amphibian Biology, Graduate School of Science, Hiroshima University, Hiroshima 734-8551, Japan

Address all correspondence and requests for reprints to: Michihiko Ito, Department of Biosciences, School of Science, Kitasato University, 1-15-1 Kitasato, Sagamihara, Japan. E-mail: ito{at}jet.sci.kitasato-u.ac.jp.

Amphibian metamorphosis induced by T₃ involves programmed cell death and the differentiation of various types of cells in degenerated and reconstructed tissues. However, the signaling pathway that directs the T₃-dependent cell-fate determinations remains unclear. TNF- is a pleiotropic cytokine that affects diverse cellular responses. Engagement of TNF- with its receptor (TNFR1) causes intracellular apoptotic and/or survival signaling. To investigate TNF signaling functions during anuran metamorphosis, we first identified Xenopus laevis orthologs of TNF (xTNF)- and its receptor. We found that xTNF- activated nuclear factor-B in X. laevis A6 cells through the Fas-associated death domain and receptor-interacting protein 1. Interestingly, xTNF- mRNA in blood cells showed prominent expression at prometamorphosis during metamorphosis. Next, to elucidate the apoptotic and/or survival signaling induced by xTNF- in an in vitro model of metamorphosis, we established a vascular endothelial cell line, XLgoo, from X. laevis tadpole tail. XLgoo cells formed actin stress fibers and elongated in response to xTNF-. T₃ induced apoptosis in these cells, but the addition of xTNF- blocked the T₃-induced apoptosis. In addition, treatment of the cells with T₃ for 2 d induced the expression of thyroid hormone receptor-β and caspase-3, and this thyroid hormone receptor-β induction was drastically repressed by xTNF-. Furthermore, in organ culture of the tail, xTNF- significantly attenuated the tail degeneration induced by T₃. These findings suggested that xTNF- could protect vascular endothelial cells from apoptotic cell death induced by T₃ during metamorphosis and thereby participate in the regulation of cell fate.