[PDF][PDF] The Toll–interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis

H Xiao, MF Gulen, J Qin, J Yao, K Bulek, D Kish… - Immunity, 2007 - cell.com
H Xiao, MF Gulen, J Qin, J Yao, K Bulek, D Kish, CZ Altuntas, D Wald, C Ma, H Zhou…
Immunity, 2007cell.com
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 …
Summary
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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