The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis |
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Authors: | Xiao Hui Gulen Muhammet Fatih Qin Jinzhong Yao Jianhong Bulek Katarzyna Kish Danielle Altuntas Cengiz Zubeyir Wald David Ma Caixia Zhou Hang Tuohy Vincent K Fairchild Robert L de la Motte Carol Cua Daniel Vallance Bruce A Li Xiaoxia |
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Institution: | Department of Immunology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. |
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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. |
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