title: The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis.
abstract: Despite constant contact with the large population of commensal bacteria, the colonic mucosa is normally hyporesponsive to these potentially proinflammatory signals. Here we report that the single immunoglobulin IL-1 receptor-related molecule (SIGIRR), a negative regulator for Toll-IL-1R signaling, plays a critical role in gut homeostasis, intestinal inflammation, and colitis-associated tumorigenesis by maintaining the microbial tolerance of the colonic epithelium. SIGIRR-deficient (Sigirr(-/-)) colonic epithelial cells displayed commensal bacteria-dependent homeostatic defects, as shown by constitutive upregulation of inflammatory genes, increased inflammatory responses to dextran sulfate sodium (DSS) challenge, and increased Azoxymethane (AOM)+DSS-induced colitis-associated tumorigenesis. Gut epithelium-specific expression of the SIGIRR transgene in the SIGIRR-deficient background reduced the cell survival of the SIGIRR-deficient colon epithelium, abrogated the hypersensitivity of the Sigirr(-/-) mice to DSS-induced colitis, and reduced AOM+DSS-induced tumorigenesis. Taken together, our results indicate that epithelium-derived SIGIRR is critical in controlling the homeostasis and innate immune responses of the colon to enteric microflora.
authors.affiliation: Department of Immunology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.forename: Muhammet Fatih
authors.initials: MF
authors.lastname: Gulen
authors.forename: Jinzhong
authors.initials: J
authors.lastname: Qin
authors.forename: Jianhong
authors.initials: J
authors.lastname: Yao
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bulek
authors.forename: Danielle
authors.initials: D
authors.lastname: Kish
authors.forename: Cengiz Zubeyir
authors.initials: CZ
authors.lastname: Altuntas
authors.forename: David
authors.initials: D
authors.lastname: Wald
authors.forename: Caixia
authors.initials: C
authors.lastname: Ma
authors.forename: Hang
authors.initials: H
authors.lastname: Zhou
authors.forename: Vincent K
authors.initials: VK
authors.lastname: Tuohy
authors.forename: Robert L
authors.initials: RL
authors.lastname: Fairchild
authors.forename: Carol
authors.initials: C
authors.lastname: de la Motte
authors.forename: Daniel
authors.initials: D
authors.lastname: Cua
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Vallance
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D001419:Bacteria / Q000276:immunology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology*; D018925:Chemokines / Q000235:genetics; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics*; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D018925:Chemokines; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D050796:STAT3 Transcription Factor; C484529:SIGIRR protein, mouse