title: Essential contribution of IRF3 to intestinal homeostasis and microbiota-mediated Tslp gene induction.
abstract: The large intestinal epithelial cells and immune cells are exposed to a variety of molecules derived from commensal microbiota that can activate innate receptors, such as Toll-like receptors (TLRs) and retinoic acid-inducible gene-I-like receptors (RLRs). Although the activation of these receptors is known to be critical for homeostasis of the large intestine, the underlying gene regulatory mechanisms are not well understood. Here, we show that IFN regulatory factor (IRF)3 is critical for the suppression of dextran sulfate sodium-induced colitis. IRF3-deficient mice exhibited lethal defects in the inflammatory and recovery phases of the colitis, accompanied by marked defects in the gene induction for thymic stromal lymphopoietin (TSLP), a cytokine known to be essential for protection of the large intestine. We further provide evidence that DNA and RNA of the large intestinal contents are critical for Tslp gene induction via IRF3 activation by cytosolic nucleic acid receptors. We also demonstrate that IRF3 indeed activates the gene promoter of Tslp via IRF-binding sequences. This newly identified intestinal gene regulatory mechanism, wherein IRF3 activated by microbiota-derived nucleic acids plays a critical role in intestinal homeostasis, may have clinical implication in colonic inflammatory disorders.
authors.affiliation: Department of Molecular Immunology, Institute of Industrial Science,  University of Tokyo, Meguro-ku, Tokyo 153-8505,  Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Negishi
authors.forename: Shoji
authors.initials: S
authors.lastname: Miki
authors.forename: Hana
authors.initials: H
authors.lastname: Sarashina
authors.forename: Naoko
authors.initials: N
authors.lastname: Taguchi-Atarashi
authors.forename: Akira
authors.initials: A
authors.lastname: Nakajima
authors.forename: Kosuke
authors.initials: K
authors.lastname: Matsuki
authors.forename: Nobuyasu
authors.initials: N
authors.lastname: Endo
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yanai
authors.forename: Junko
authors.initials: J
authors.lastname: Nishio
authors.forename: Kenya
authors.initials: K
authors.lastname: Honda
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
mesh_terms: D000818:Animals; D003092:Colitis / Q000382:microbiology; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D006706:Homeostasis; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000502:physiology*; D007422:Intestines / Q000382:microbiology*; D054892:Metagenome; D051379:Mice; D008954:Models, Biological; D012313:RNA / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D014212:Tretinoin; D012313:RNA; D004247:DNA; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse