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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1506.)
© 2000 American Heart Association, Inc.

Vascular Biology

Nitric Oxide Enhances Expression and Shedding of Tumor Necrosis Factor Receptor I (p55) in Endothelial Cells

Masaki Okuyama; Seiji Yamaguchi; Minako Yamaoka; Joji Nitobe; Satoshi Fujii; Tetsuhiko Yoshimura; Hitonobu Tomoike

From the First Department of Internal Medicine (M.O., S.Y., M.Y., J.N., H.T.), Yamagata University School of Medicine, and the Institute for Life Support Technology (S.F., T.Y.), Yamagata Technopolis Foundation, Yamagata, Japan.

Correspondence to Seiji Yamaguchi, MD, First Department of Internal Medicine, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan. E-mail syamaguc{at}med id. yamagata-u.ac.jp

Abstract—The biological actions of tumor necrosis factor- (TNF-) are mediated by 2 distinct receptors, TNF-RI (p55) and TNF-RII (p75). The extracellular domains of both receptors are shed in soluble form (sTNF-RI and sTNF-RII). The soluble receptors are involved in regulating TNF- activities and may have therapeutic potential as TNF-neutralizing agents. However, it remains unclear as to what kind of physiological molecule can regulate TNF receptors. Nitric oxide (NO) mediates a variety of biological and pathophysiological functions. We hypothesized that NO may modulate the expression and shedding of TNF-RI. An NO donor, diethylamine/NO complex (NOC 5), increased sTNF-RI in the supernatants of ECV304, a human umbilical vein cell line, in a dose-dependent manner. TNF-RI mRNA in these cells was upregulated by NOC 5. 8-Br-cGMP and peroxynitrate had no effect on sTNF-RI release. Genistein and herbimycin A, inhibitors of tyrosine kinase, inhibited sTNF-RI release. Herbimycin A inhibited the levels of TNF-RI mRNA enhanced by NOC 5, which downregulated the surface expression of TNF-RI, indicating that NO is also involved in the shedding process of TNF-RI. The shedding of TNF-RI was abolished by a synthetic inhibitor of matrix metalloproteinase, KB-R8301. In conclusion, NO enhanced the release of sTNF-RI from endothelial cells by a cGMP-independent mechanism. Dual pathways suggested for NO-induced sTNF-RI release include (1) enhanced expression of TNF-RI, at least partially, by a tyrosine kinase–dependent mechanism and (2) increased shedding of TNF-RI by a type of metalloproteinase.

Key Words: nitric oxide • TNF- • TNF receptor (p55) • human endothelial cells • tyrosine kinase inhibitor

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