Alternative titles; symbols
HGNC Approved Gene Symbol: SIGIRR
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38) : 11:405,716-417,397 (from NCBI)
Toll-like receptor (TLR; see 603028) and interleukin-1 receptor (IL1R; 147810) family members mediate inflammatory signals that activate nuclear factor kappa-B (NFKB; see 164011) or mitogen-activated protein kinase (MAPK; see 602425) pathways. By searching an EST database using the IL1R signaling domain as the probe, followed by screening human and mouse cDNA libraries, Thomassen et al. (1999) obtained cDNAs encoding mouse and human SIGIRR. The deduced 410-amino acid human protein, which is 82% identical to the mouse sequence and 23% identical to IL1R, has no signal peptide and contains a short 118-amino acid single immunoglobulin (Ig) extracellular domain with 4 potential N-glycosylation sites; a transmembrane region; and a 268-amino acid cytoplasmic tail with 4 IL1R-like signaling motifs. However, 2 changes in the regions conserved with IL1R (ser447 in IL1R replaced by cys222 in motif 3 of SIGIRR, and tyr536 in IL1R replaced by leu305 in motif 4 of SIGIRR) are predicted to abrogate signaling capabilities. Northern blot analysis revealed wide but differential expression of predominant 2.4- and 1.5-kb transcripts and minor 4.4- and 0.9-kb transcripts in all tissues tested. RT-PCR analysis detected SIGIRR expression in all cell lines tested. Western blot analysis showed expression of a 50- to 80-kD protein in the membrane fraction of transfected cells; glycosidase treatment resulted in the expression of a 48-kD protein.
By RNA blot analysis, Wald et al. (2003) examined expression of SIGIRR. In mouse tissues, Sigirr was highly expressed in kidney, moderately expressed in colon, small intestine, lung, spleen, and liver, and weakly or not expressed in brain and muscle. Expression in mouse and human cells was more specific, with high expression in epithelial cell lines, moderate expression in splenocytes, and low or undetectable expression in fibroblast and endothelial cell lines. No expression was detected in bone-derived macrophages.
Garlanda et al. (2004) found that mouse and human immature dendritic cells expressed high levels of SIGIRR, which they called TIR8. Expression of SIGIRR was downregulated following LPS exposure.
By reporter assay analysis of chimeric IL1R-SIGIRR constructs, Thomassen et al. (1999) confirmed that the cytoplasmic domain of SIGIRR is unable to mediate activation of the IL8 (146930) promoter or of NFKB. Surface plasmon resonance (BIAcore) analysis determined that SIGIRR is unable to bind IL1A (147760), IL1B (147720), or IL1RA (147679). Thomassen et al. (1999) concluded that in spite of structural similarities with IL1R, SIGIRR is not a part of the IL1-binding and -signaling complex.
Wald et al. (2003) observed expression of the inflammatory marker Mip2 (CXCL2; 139110) and downregulation of Sigirr in mice after low-dose injection of lipopolysaccharide (LPS) in several tissues, including kidney and lung. Overexpression of SIGIRR in human lymphocyte and liver cell lines reduced IL1- and IL18 (600953)-mediated activation of NFKB, but not IFNG (147570)-mediated activation of STAT1 (600555). By replacing exons 2 through 5 of the Sigirr gene by homologous recombination, Wald et al. (2003) generated healthy Sigirr-deficient mice. Sigirr -/- mice had an increased inflammatory response after injection of the TLR4 (603030) activator LPS, and they had a lower threshold to lethal endotoxin challenge. The mutant mice were hyperresponsive to IL1, but not TNF (191160). Primary cell lines from Sigirr-deficient mice showed a similar phenotype in response to LPS and to CpG dinucleotides, which activate TLR9 (605474). Coimmunoprecipitation analysis showed that SIGIRR strongly dimerized with itself and with TLR4, TLR5 (603031), and TLR9, but most strongly with IL1R. It also dimerized with TRAF6 (602355) and IRAK (see 300283), but not with other TRAF proteins. Mutation analysis indicated that residues 248 to 298 of SIGIRR are essential for interaction with TLR4 and TRAF6. Wald et al. (2003) concluded that, in specific cell types, SIGIRR acts as a negative regulator of TLR-IL1R signaling, possibly in a manner reminiscent of IRAKM (IRAK3; 604459), which inhibits the dissociation of the receptor-proximal signaling complex.
Molgora et al. (2017) reported that IL-1R8 serves as a checkpoint for natural killer (NK) cell maturation and effector function. Its genetic blockade unleashes NK cell-mediated resistance to hepatic carcinogenesis, hematogenous liver and lung metastasis, and cytomegalovirus infection.
By radiation hybrid analysis, Thomassen et al. (1999) mapped the SIGIRR gene to 11p15.5, a localization distinct from other IL1R family members but in the same region as Beckwith-Wiedemann syndrome (BWS; 130650) and distal arthrogryposis type 2B (AMCD2B; 601680).
Garlanda et al. (2004) found that Sigirr-deficient mice had normal susceptibility to systemic LPS toxicity and to intraperitoneal or subcutaneous inflammation, but they were more susceptible than normal controls to intestinal inflammation.
Xiao et al. (2007) found that colonic epithelial cells from Sigirr-deficient mice displayed constitutive upregulation of inflammatory genes, increased inflammatory responses to challenge with dextran sulfate sodium (DSS), and increased colitis-associated tumorigenesis induced by DSS and azoxymethane (DSS+AOM). Introduction of Sigirr into the gut epithelium of Sigirr-deficient mice reduced cell survival of colon epithelium and abrogated the sensitivity of Sigirr-deficient mice to DSS-induced colitis and AOM+DSS-induced tumorigenesis. Xiao et al. (2007) concluded that epithelium-derived SIGIRR is critical to controlling homeostasis and innate immune responses in colon to potentially proinflammatory signals present in commensal enteric bacteria.
Garlanda, C., Riva, F., Polentarutti, N., Buracchi, C., Sironi, M., De Bortoli, M., Muzio, M., Bergottini, R., Scanziani, E., Vecchi, A., Hirsch, E., Mantovani, A. Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family. Proc. Nat. Acad. Sci. 101: 3522-3526, 2004. [PubMed: 14993616] [Full Text: https://doi.org/10.1073/pnas.0308680101]
Molgora, M., Bonavita, E., Ponzetta, A., Riva, F., Barbagallo, M., Jaillon, S., Popovic, B., Bernardini, G., Magrini, E., Gianni, F., Zelenay, S., Jonjic, S., Santoni, A., Garlanda, C., Mantovani, A. IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity. Nature 551: 110-114, 2017. [PubMed: 29072292] [Full Text: https://doi.org/10.1038/nature24293]
Thomassen, E., Renshaw, B. R., Sims, J. E. Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily. Cytokine 11: 389-399, 1999. [PubMed: 10346978] [Full Text: https://doi.org/10.1006/cyto.1998.0452]
Wald, D., Qin, J., Zhao, Z., Qian, Y., Naramura, M., Tian, L., Towne, J., Sims, J. E., Stark, G. R., Li, X. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nature Immun. 4: 920-927, 2003. [PubMed: 12925853] [Full Text: https://doi.org/10.1038/ni968]
Xiao, H., Gulen, M. F., Qin, J., Yao, J., Bulek, K., Kish, D., Altuntas, C. Z., Wald, D., Ma, C., Zhou, H., Tuohy, V. K., Fairchild, R. L., de la Motte, C., Cua, D., Vallance, B. A., Li, X. The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis. Immunity 26: 461-475, 2007. [PubMed: 17398123] [Full Text: https://doi.org/10.1016/j.immuni.2007.02.012]