{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:43:25Z","timestamp":1790873005790,"version":"4.1.0"},"reference-count":0,"publisher":"Rockefeller University Press","issue":"6","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1990,12,1]]},"abstract":"<jats:p>The present study demonstrates that murine dermal fibroblasts produce nitrite (NO2-) and nitrate (NO3-) upon treatment with interferon gamma (IFN-gamma). This formation is dependent on L-arginine and can be inhibited by the L-arginine analogue NG-monomethyl-L-arginine. The effect of IFN-gamma is drastically increased by cotreatment with tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1), or lipopolysaccharide (LPS). The tested cytokines also induce formation of tetrahydrobiopterin in murine fibroblasts. Inhibition of guanosine triphosphate-cyclohydrolase I, the key enzyme of tetrahydrobiopterin de novo synthesis with 2,4-diamino-6-hydroxy-pyrimidine, leads to decreased formation of NO2- and NO3-. This effect can be reversed by addition of sepiapterin, which provides tetrahydrobiopterin via a salvage pathway. Methotrexate, which inhibits the salvage pathway, blocks the restoration of NO2- and NO3- production by sepiapterin. The cytotoxic effect of combinations of IFN-alpha with TNF-gamma, IL-1, or LPS is attenuated by inhibition of tetrahydrobiopterin synthesis. These results show that intracellular concentrations of tetrahydrobiopterin control the amount of NO2- and NO3- produced in situ and suggest that the role of cytokine-induced tetrahydrobiopterin synthesis is to provide cells with the active cofactor for production of nitrogen oxides.<\/jats:p>","DOI":"10.1084\/jem.172.6.1599","type":"journal-article","created":{"date-parts":[[2004,6,24]],"date-time":"2004-06-24T07:56:10Z","timestamp":1088063770000},"page":"1599-1607","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":218,"title":["Tetrahydrobiopterin-dependent formation of nitrite and nitrate in murine fibroblasts."],"prefix":"10.1084","volume":"172","author":[{"given":"G","family":"Werner-Felmayer","sequence":"first","affiliation":[{"name":"Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E R","family":"Werner","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Hausen","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Reibnegger","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H","family":"Wachter","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[1990,12,1]]},"container-title":["The Journal of experimental medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/172\/6\/1599\/1671571\/1599.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/172\/6\/1599\/1671571\/1599.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T01:50:54Z","timestamp":1690249854000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/172\/6\/1599\/24764\/Tetrahydrobiopterin-dependent-formation-of-nitrite"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1990,12,1]]},"references-count":0,"journal-issue":{"issue":"6","published-print":{"date-parts":[[1990,12,1]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.172.6.1599","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[1990,12,1]]}}}