title: Nitric oxide enhances expression and shedding of tumor necrosis factor receptor I (p55) in endothelial cells.
abstract: The biological actions of tumor necrosis factor-alpha (TNF-alpha) 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-alpha 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.
authors.affiliation: First Department of Internal Medicine, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Okuyama
authors.forename: S
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: M
authors.initials: M
authors.lastname: Yamaoka
authors.forename: J
authors.initials: J
authors.lastname: Nitobe
authors.forename: S
authors.initials: S
authors.lastname: Fujii
authors.forename: T
authors.initials: T
authors.lastname: Yoshimura
authors.forename: H
authors.initials: H
authors.lastname: Tomoike
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism*; D002461:Cell Line, Transformed; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D006877:Hydroxamic Acids; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D014226:Triazenes / Q000494:pharmacology; D014471:Umbilical Veins
chemical_list: C114535:1-hydroxy-2-oxo-3-(3-aminopropyl)-3-isopropyl-1-triazene; D015703:Antigens, CD; D006877:Hydroxamic Acids; C423012:KB R8301; D020030:Nitric Oxide Donors; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014226:Triazenes; D015124:8-Bromo Cyclic Adenosine Monophosphate; D009569:Nitric Oxide