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Roles of Stat1, Stat2, and Interferon Regulatory Factor-9 (IRF-9) in Interferon Tau Regulation of IRF-1¹

^a Center for Animal Biotechnology and Genomics, Department of Animal Science, Texas A&M University, College Station, Texas 77843 ^b Departments of Medicine, Molecular and Cellular Biology, and Immunology, Baylor College of Medicine, Houston, Texas 77030

Interferon tau (IFN) is the pregnancy recognition signal produced by the conceptus trophectoderm and acts in a paracine manner on the ovine endometrium to increase expression of IFN-stimulated genes primarily in the stroma and deep glandular epithelium, including IFN regulatory factor-1 (IRF-1). The roles of Stat1, Stat2, and IRF-9 in IFN regulation of IRF-1 expression were determined using human stromal fibroblasts lacking specific IFN signaling components or complemented with specific Stat1 mutants. In parental (2fTGH) cells treated with IFN, Stat1/ß was tyrosine phosphorylated by 15 min, and IRF-1 mRNA and protein increased from 0 to 6 h, was maximal at 6 h, and decreased to 24 h. In contrast, IFN did not affect IRF-1 expression in Stat1- and Stat2-deficient cells or in Stat1-deficient cells complemented with Stat1 Y701Q or Stat1 R602L mutants. In Stat1-deficient cells complemented with the Stat1 S727A mutant, Stat1, or Stat1ß and treated with IFN, IRF-1 increased from 0 to 6 h, was maximal at 6 h, and decreased thereafter. In IRF-9-deficient cells stimulated with IFN, IRF-1 increased from 0 to 6 h but did not exhibit the sharp decline from 6 to 12 h observed in other cells. Collectively, results indicate that IFN effect on IRF-1 expression is primarily regulated by tyrosine-phosphorylated Stat1 or Stat1ß dimers, whereas the decline of IRF-1 after 6 h of IFN treatment is regulated by IRF-9.

First decision: 9 September 2001.

¹ This work was supported by NIH grant 2R01-HD32534 (to F.W.B. and T.E.S.) and in part by NIH grants F32-HD08501 (to G.A.J.) and P30 ES09106.

² Correspondence: Thomas E. Spencer, Center for Animal Biotechnology and Genomics, 442C Kleberg Center, 2471 TAMU, Texas A&M University, College Station, TX 77843-2471. FAX: 979 862 2662; tspencer{at}tamu.edu

³ Current address: Department of Animal and Veterinary Science, Center for Reproductive Biology, University of Idaho, Moscow, ID 83844-2330.

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