title: Down-regulation of single immunoglobulin interleukin-1R-related molecule (SIGIRR)/TIR8 expression in intestinal epithelial cells during inflammation.
abstract: Single immunoglobulin (Ig) interleukin-1R-related molecule (SIGIRR) is an Ig-like membrane protein critical for negative regulation of Toll-like receptor (TLR)-4-mediated signalling. We investigated SIGIRR expression and its regulation mechanism in intestinal epithelial cells (IECs) during inflammation. Endoscopic biopsy specimens were obtained from active and inactive colonic mucosa of ulcerative colitis (UC) patients, then SIGIRR expression was examined using real-time polymerase chain reaction (PCR) and immunohistochemistry (IH). Mice experimental colitis models were established by administrations of sulphonic acid (TNBS) and dextran sodium sulphate (DSS), and epithelial expression of SIGIRR was examined using real-time PCR, IH and flow cytometry. The effects of lipopolysaccharide (LPS) and tumour necrosis factor (TNF)-α on SIGIRR expression were evaluated in vitro using cultured IECs. To elucidate SIGIRR expression regulation in IECs, binding ability of the transcription factor SP1 at the responsive element of the SIGIRR promoter was examined using gel-shift and chromatin immunoprecipitation (ChIP) assays. In human colonic samples, SIGIRR was expressed mainly in IECs at levels significantly higher in inactive compared to active mucosa. In the mice, SIGIRR colonic expression decreased rapidly after colitis development and returned gradually to basal levels. Experimental colitis-mediated down-regulation of SIGIRR in IECs was also confirmed by IH and flow cytometry results. Further, inflammatory conditions induced by TLR ligands and TNF-α caused significant down-regulation of SIGIRR expression in IECs, which was dependent upon decreased SP1 binding at the responsive element of the SIGIRR promoter. We found that SIGIRR is expressed in IECs and serves as a negative regulator to maintain gut innate immunity, which is down-regulated during inflammation by inhibition of an SP1-mediated pathway.
authors.affiliation: Department of Internal Medicine II, Shimane University School of Medicine, Shimane University Hospital, Izumo, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Kadota
authors.forename: S
authors.initials: S
authors.lastname: Ishihara
authors.forename: M M
authors.initials: MM
authors.lastname: Aziz
authors.forename: M A
authors.initials: MA
authors.lastname: Rumi
authors.forename: N
authors.initials: N
authors.lastname: Oshima
authors.forename: Y
authors.initials: Y
authors.lastname: Mishima
authors.forename: I
authors.initials: I
authors.lastname: Moriyama
authors.forename: T
authors.initials: T
authors.lastname: Yuki
authors.forename: Y
authors.initials: Y
authors.lastname: Amano
authors.forename: Y
authors.initials: Y
authors.lastname: Kinoshita
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism*; D003093:Colitis, Ulcerative / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000276:immunology*; D004847:Epithelial Cells / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007420:Intestine, Large / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017472:Receptors, Interleukin-1; D016329:Sp1 Transcription Factor; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C546891:SIGIRR protein, human; C484529:SIGIRR protein, mouse; C493487:Tlr4 protein, mouse