title: RANK signaling induces interferon-stimulated genes in the fetal thymic stroma.
abstract: Medullary thymic epithelial cells (mTECs) are essential for thymic negative selection to prevent autoimmunity. Previous studies show that mTEC development is dependent on the signal transducers TRAF6 and NIK. However, the downstream target genes of signals controlled by these molecules remain unknown. We performed a microarray analysis on mRNAs down-regulated by deficiencies in TRAF6 or functional NIK in an in vitro organ culture of fetal thymic stromata (2DG-FTOC). An in silico analysis of transcription factor binding sites in plausible promoter regions of differentially expressed genes suggests that STAT1 is involved in TRAF6- and NIK-dependent gene expression. Indeed, the signal of RANK, a TNF receptor family member that activates TRAF6 and NIK, induces the activation of STAT1 in 2DG-FTOC. Moreover, RANK signaling induces the up-regulation of interferon (IFN)-stimulated gene (ISG) expression, suggesting that the RANKL-dependent activation of STAT1 up-regulates ISG expression. The RANKL-dependent expression levels of ISGs were reduced but not completely abolished in interferon α receptor 1-deficient (Ifnar1(-/-)) 2DG-FTOC. Our data suggest that RANK signaling induces ISG expression in both type I interferon-independent and interferon-dependent mechanisms.
authors.affiliation: Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ohshima
authors.forename: Junwen
authors.initials: J
authors.lastname: Qin
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Konno
authors.forename: Akihisa
authors.initials: A
authors.lastname: Hirosawa
authors.forename: Takuma
authors.initials: T
authors.lastname: Shiraishi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yanai
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shimo
authors.forename: Miho
authors.initials: M
authors.lastname: Shinzawa
authors.forename: Nobuko
authors.initials: N
authors.lastname: Akiyama
authors.forename: Riu
authors.initials: R
authors.lastname: Yamashita
authors.forename: Kenta
authors.initials: K
authors.lastname: Nakai
authors.forename: Taishin
authors.initials: T
authors.lastname: Akiyama
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Inoue
mesh_terms: D000818:Animals; D004847:Epithelial Cells / Q000276:immunology*; D005333:Fetus; D005786:Gene Expression Regulation; D007370:Interferon Type I / Q000276:immunology*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D017634:Self Tolerance / Q000235:genetics*; D015398:Signal Transduction; D017154:Stromal Cells / Q000276:immunology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D007370:Interferon Type I; D017346:Protein Serine-Threonine Kinases; D053246:Receptor Activator of Nuclear Factor-kappa B; D053633:Receptor, Interferon alpha-beta; D048029:TNF Receptor-Associated Factor 6; D000097782:NF-kappaB-Inducing Kinase; C505687:Tnfrsf11a protein, mouse