Alternative titles; symbols
HGNC Approved Gene Symbol: IL1RL1
Cytogenetic location: 2q12.1 Genomic coordinates (GRCh38) : 2:102,311,563-102,352,356 (from NCBI)
IL1RL1 is an IL1 (see 147760) family receptor that is selectively expressed on T helper-2 (Th2) cells and mast cells. It mediates the biologic effects of IL33 (608678), a member of the IL1 family that potently drives production of Th2-associated cytokines (e.g., IL4; 147780) (summary by Yagami et al., 2010).
Tominaga (1989) isolated a murine gene, which they termed St2, as one of the genes specifically expressed by growth stimulation in BALB/c-3T3 cells. The gene encodes 2 protein products: St2, the soluble secreted form; and St2L, the transmembrane receptor form, which is very similar to the interleukin-1 receptors (147810; 147811) that map to human chromosome 2. Tominaga (1989) suggested that St2 gene expression is related to the growth of cells and that an unknown signal is transduced to control cell proliferation by binding of specific ligand(s). Because the symbol ST2 had already been assigned to a locus on 11p (see 185440), the HUGO Nomenclature Committee designated the human homolog of the mouse St2 gene as IL1RL1.
By use of a mouse St2 probe to screen an activated human helper T-cell line library, Tominaga et al. (1992) isolated a cDNA for IL1RL1, which encodes a 328-amino acid protein with 9 potential glycosylation sites and 3 Ig-like domains. By Northern blot analysis, Kumar et al. (1997) detected expression of a 1.4-kb IL1RL1 transcript in skeletal muscle, heart, brain, and pancreas, with additional 2.5- and 4.2-kb transcripts in lung, liver, placenta, and kidney. By RT-PCR analysis, they observed constitutive expression in mesenchymal and myeloblastic cell lines, with further induction by phorbol ester or cytokine stimulation. Expression in mouse, in contrast, occurs only between days 2 and 4 after exposure to UVB irradiation.
Tago et al. (2001) found that a third splice variant of IL1RL1, ST2V, has an additional exon, designated 5E, and encodes a protein with a predicted molecular mass of 30 kD. Transfection of ST2V into COS-7 cells resulted in expression of a glycosylated protein with an apparent molecular mass of 40 kD. Using confocal laser microscopy, they localized ST2V to the plasma membrane. RT-PCR with primers designed to amplify exon 5E indicated expression in colon, stomach, small intestine, lung, spleen, testis, and placenta, and no expression in brain, heart, liver, kidney, and skeletal muscle. Tago et al. (2001) noted that this pattern of expression is different from that of IL1RL1 or ST2L.
Brint et al. (2004) noted that, unlike most members of the Toll (see TLR4; 603030)-IL1R (TIR) superfamily, IL1RL1 does not induce an inflammatory response or activate NFKB (see 164011), although it does activate MAP kinases. IL1RL1 is present on Th2 but not Th1 T lymphocytes, and neutralization of IL1RL1 enhances Th1 cell responses and inhibits allergic airway inflammation. Using macrophages from Il1rl1 -/- mice, Brint et al. (2004) detected enhanced production of proinflammatory cytokines in response to IL1A (147760), IL1B (147720), lipopolysaccharide (LPS), a TLR4 ligand, bacterial lipoprotein, a TLR2 (603028) ligand, and CpG, a TLR9 (605474) ligand, but not to poly(I:C), a TLR3 (603029) ligand. These results suggested that Il1rl1 is a negative regulator of IL1R1 (147810), TLR2, TLR4, and TLR9 signaling. Cotransfection of Il1rl1 into cells overexpressing Myd88 (602170) or Mal (606252) inhibited Myd88/Mal-induced NFKB activation in a dose-dependent manner. GST-fusion proteins containing the TIR domain of Il1rl1 were able to interact with Mal or Myd88, suggesting that IL1RL1 inhibition of TLR4 and IL1R1 signaling may be due to the sequestration of these downstream signaling components by IL1RL1. Brint et al. (2004) proposed that IL1RL1 is necessary for endotoxin tolerance and, by inhibiting TLR responses, enhances Th2 responses.
Using immunoprecipitation, immunoblot, and pull-down analyses, Schmitz et al. (2005) showed that IL33 (608678) bound to ST2. NFKB-dependent reporter assays and flow cytometry demonstrated that IL33 signaled through ST2. Immunoprecipitation and Western blot analysis of transfected cells and ST2-expressing mast cells showed that IL33 stimulation recruited MYD88, IRAK (300283), IRAK4 (606883), and TRAF6 (602355), followed by phosphorylation of ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948), p38 (MAPK14; 600289), and JNK (see 601158). Addition of IL33 to polarized mouse Th2 lymphocytes expressing St2 resulted in increased production of Il5 (147850) and Il13 (147683), whereas IL33 reduced the level of Ifng (147570) produced by polarized mouse Th1 cells.
Chackerian et al. (2007) found that mice lacking Il1racp (IL1RAP; 602626) had no response to Il33, whereas wildtype displayed potent inflammatory effects, including massive blood eosinophilia, increased Il5 and IgE serum levels, goblet cell hyperplasia at mucosal surfaces, and enlarged spleen and lymph nodes. Biacore analysis showed that Il33 interacted directly with St2, but not with Il1racp. ELISA showed that St2, Il33, and Il1racp formed a ligand/receptor complex, and a dominant-negative experiment revealed that Il1racp acted as a signaling receptor subunit in the complex.
Using immunohistochemistry, Xu et al. (2008) demonstrated that synovial membranes from rheumatoid arthritis (RA; 180300) patients expressed both IL33 and ST2 in the lining layer and the interstitial sublining layers. Immunohistochemical and RT-PCR analyses showed that primary synovial fibroblasts from these patients expressed IL33 only after addition of TNF (191160) and IL1B.
Using mice with a naturally occurring Ncf1 (608512) mutation reported by Hultqvist et al. (2004) and rat type II collagen (CII), which, like human CII (COL2A1; 120140), differs from the mouse sequence only at residue 266, Hagenow et al. (2009) examined arthritis in a mouse model that did not require the use of adjuvant. Mutant mice produced lower levels of reactive oxygen species (ROS), but increased levels of autoantibodies and greater numbers of T cells expressing Il33r. With impaired T-cell tolerance of tissue-specific CII, the mice developed severe arthritis. Hagenow et al. (2009) concluded that insufficient ROS production promotes breakdown of immune tolerance and development of autoimmune and adjuvant-free arthritis through an IL5- and IL33R-dependent T-cell activation pathway.
By RT-PCR analysis of cultured human lung cell subpopulations, Yagami et al. (2010) detected IL33R expression in endothelial and epithelial cells, but not in fibroblasts or smooth muscle cells. IL33 induced IL8 (146930) expression in IL33R-positive cells, which could be inhibited by IL33R small interfering RNA and, on epithelial cells only, corticosteroid treatment. IL4 and IL13 enhanced IL33R expression. IL33 induced activation of ERK in epithelial cells and both ERK and p38 in endothelial cells. Yagami et al. (2010) proposed that IL33-mediated inflammatory responses of lung tissue cells may be involved in chronic allergic inflammation of the asthmatic airway.
Using flow cytometry and immunoblot analysis, Fock et al. (2013) found that human placental and decidual macrophages expressed IL33 and that various trophoblast subtypes expressed IL33R. IL33 enhanced growth of first-trimester placental explants and proliferation of extravillous trophoblasts through activation of AKT1 (164730) and ERK1/ERK2. Soluble ST2 inhibited these activities. Fock et al. (2013) concluded that IL33 is a macrophage-derived regulator of placental growth during early pregnancy.
In mice, Schiering et al. (2014) showed that the IL33 receptor ST2 is preferentially expressed on colonic T-regulatory (T-reg) cells, where it promotes T-reg function and adaptation to the inflammatory environment. IL33 signaling in T cells stimulates T-reg responses in several ways: first, it enhances TGFB1 (190180)-mediated differentiation of T-reg cells, and second, it provides a necessary signal for T-reg cell accumulation and maintenance in inflamed tissues. Strikingly, IL23 (see 605580), a key proinflammatory cytokine in the pathogenesis of inflammatory bowel disease (IBD; see 266600), restrained T-reg responses through inhibition of IL33 responsiveness. Schiering et al. (2014) concluded that these results demonstrated a hitherto unrecognized link between an endogenous mediator of tissue damage and a major antiinflammatory pathway, and suggested that the balance between IL33 and IL23 may be a key controller of intestinal immune responses.
Using flow cytometric analysis, Tsuzuki et al. (2016) demonstrated expression of Il33r, a heterodimer of St2 and IL1rap, on mouse eosinophil, basophil, and mast cell progenitor cells, but not on their precursor, granulocyte/monocyte progenitors. Megakaryocyte/erythrocyte progenitors, but not lymphoid progenitors, also expressed both components of Il33r. Stimulation of eosinophil, basophil, and mast cell progenitor cells with Il33 induced gene and protein expression of Th2 and proinflammatory cytokines and chemokines associated with allergic inflammation. The progenitor populations produced higher levels of cytokines than mature cells. Il33 did not induce proliferation of the progenitor cells in vitro, but it induced an eosinophil progenitor expansion followed by eosinophilia in vivo in an Il5-dependent manner. Tsuzuki et al. (2016) concluded that eosinophil, basophil, and mast cell progenitor cells are sources of both allergy-related granulocytes and cytokines in IL33-induced inflammation.
Tominaga et al. (1996) assigned the human IL1RL1 gene to chromosome 2 by analysis of human/rodent somatic cell hybrids. They refined the assignment to 2q11.2 by fluorescence in situ hybridization. The gene is very tightly linked to IL1R1 (147810). Together with the structural similarity of IL1RL1 to IL1R1, the findings suggested to the authors a functional relationship between these 2 genes. Sims et al. (1995) mapped the IL1RL1 gene to 2q12 by inclusion within a YAC contig.
Dale and Nicklin (1999) showed by radiation hybrid mapping that IL1R2 (147811), IL1R1, IL1RL2 (604512), IL1RL1, and IL18R1 (604494) map to 2q12 and are transcribed in the same direction, with IL1R2 being transcribed towards the cluster.
Shimizu et al. (2005) found a significant genetic association between atopic dermatitis (ATOD; 603165) and a -26999G/A SNP (P-value = 0.000007; odds ratio 1.86) in the distal promoter region of the IL1RL1 gene in a study of 452 ATOD patients and 636 healthy controls. The -26999A allele common among ATOD patients positively regulated the transcriptional activity of ST2. In addition, having at least one -26999A allele correlated with high soluble ST2 concentrations and high total IgE levels in the sera from ATOD patients. Shimizu et al. (2005) concluded that the -26999A allele of the IL1RL1 gene is correlated with an increased risk for atopic dermatitis.
Xu et al. (2008) found that St2 -/- mice exhibited attenuated induction of collagen-induced arthritis (CIA), a model for RA, as well as reduced production of Il17 (603149), Ifng, and Tnf in vitro and serum anti-type II collagen IgG2a. Il33 administration exacerbated CIA, but did not affect disease incidence, in wildtype mice, but not in St2 -/- mice. Treatment of wildtype mast cells, but not those from St2 -/- mice, with Il33 induced production of proinflammatory cytokines and chemokines, including Il13. Mice lacking St2 and engrafted with wildtype mast cells showed exacerbated CIA when treated with Il33. Xu et al. (2008) concluded that IL33 is a critical proinflammatory cytokine for joint disease that integrates fibroblast activation with downstream immune activation via an IL33-driven, mast cell-dependent pathway. They suggested that IL33 may be a therapeutic target for RA.
Buckley et al. (2011) found that St2 -/- mice were more susceptible to polymicrobial sepsis induced by cecal ligation and puncture. The increased susceptibility was associated with impaired phagosome maturation and Nox2 (CYBB; 300481) function, which is required for reactive oxygen species production. Peritoneal leukocyte accumulation and phagocytic receptor expression were identical in St2 -/- and wildtype mice.
Brint, E. K., Xu, D., Liu, H., Dunne, A., McKenzie, A. N. J., O'Neill, L. A. J., Liew, F. Y. ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nature Immun. 5: 373-379, 2004. [PubMed: 15004556] [Full Text: https://doi.org/10.1038/ni1050]
Buckley, J. M., Liu, J. H., Li, C. H., Blankson, S., Wu, Q. D., Jiang, Y., Redmond, H. P., Wang, J. H. Increased susceptibility of ST2-deficient mice to polymicrobial sepsis is associated with an impaired bactericidal function. J. Immun. 187: 4293-4299, 2011. [PubMed: 21911606] [Full Text: https://doi.org/10.4049/jimmunol.1003872]
Chackerian, A. A., Oldham, E. R., Murphy, E. E., Schmitz, J., Pflanz, S., Kastelein, R. A. IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex. J. Immun. 179: 2551-2555, 2007. [PubMed: 17675517] [Full Text: https://doi.org/10.4049/jimmunol.179.4.2551]
Dale, M., Nicklin, M. J. Interleukin-1 receptor cluster: gene organization of IL1R2, IL1R1, IL1RL2 (IL-1Rrp2), IL1RL1 (T1/ST2), and IL18R1 (IL-1Rrp) on human chromosome 2q. Genomics 57: 177-179, 1999. [PubMed: 10191101] [Full Text: https://doi.org/10.1006/geno.1999.5767]
Fock, V., Mairhofer, M., Otti, G. R., Hiden, U., Spittler, A., Zeisler, H., Fiala, C., Knofler, M., Pollheimer, J. Macrophage-derived IL-33 is a critical factor for placental growth. J. Immun. 191: 3734-3743, 2013. [PubMed: 23997215] [Full Text: https://doi.org/10.4049/jimmunol.1300490]
Hagenow, K., Gelderman, K. A., Hultqvist, M., Merky, P., Backlund, J., Frey, O., Kamradt, T., Holmdahl, R. Ncf1-associated reduced oxidative burst promotes IL-33R+ T cell-mediated adjuvant-free arthritis in mice. J. Immun. 183: 874-881, 2009. [PubMed: 19553535] [Full Text: https://doi.org/10.4049/jimmunol.0900966]
Hultqvist, M., Olofsson, P., Holmberg, J., Backstrom, B. T., Tordsson, J., Holmdahl, R. Enhanced autoimmunity, arthritis, and encephalomyelitis in mice with a reduced oxidative burst due to a mutation in the Ncf1 gene. Proc. Nat. Acad. Sci. 101: 12646-12651, 2004. [PubMed: 15310853] [Full Text: https://doi.org/10.1073/pnas.0403831101]
Kumar, S., Tzimas, M. N., Griswold, D. E., Young, P. R. Expression of ST2, an interleukin-1 receptor homologue, is induced by proinflammatory stimuli. Biochem. Biophys. Res. Commun. 235: 474-478, 1997. [PubMed: 9207179] [Full Text: https://doi.org/10.1006/bbrc.1997.6810]
Schiering, C., Krausgruber, T., Chomka, A., Frohlich, A., Adelmann, K., Wohlfert, E. A., Pott, J., Griseri, T., Bollrath, J., Hegazy, A. N., Harrison, O. J., Owens, B. M. J., Lohning, M., Belkaid, Y., Fallon, P. G., Powrie, F. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 513: 564-568, 2014. [PubMed: 25043027] [Full Text: https://doi.org/10.1038/nature13577]
Schmitz, J., Owyang, A., Oldham, E., Song, Y., Murphy, E., McClanahan, T. K., Zurawski, G., Moshrefi, M., Qin, J., Li, X., Gorman, D. M., Bazan, J. F., Kastelein, R. A. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23: 479-490, 2005. [PubMed: 16286016] [Full Text: https://doi.org/10.1016/j.immuni.2005.09.015]
Shimizu, M., Matsuda, A., Yanagisawa, K., Hirota, T., Akahoshi, M., Inomata, N., Ebe, K., Tanaka, K., Sugiura, H., Nakashima, K., Tamari, M., Takahashi, N., Obara, K., Enomoto, T., Okayama, Y., Gao, P.-S., Huang, S.-K., Tominaga, S., Ikezawa, Z., Shirakawa, T. Functional SNPs in the distal promoter of the ST2 gene are associated with atopic dermatitis. Hum. Molec. Genet. 14: 2919-2927, 2005. [PubMed: 16118232] [Full Text: https://doi.org/10.1093/hmg/ddi323]
Sims, J. E., Painter, S. L., Gow, I. R. Genomic organization of the type I and type II IL-1 receptors. Cytokine 7: 483-490, 1995. [PubMed: 8580363] [Full Text: https://doi.org/10.1006/cyto.1995.0066]
Tago, K., Noda, T., Hayakawa, M., Iwahana, H., Yanagisawa, K., Yashiro, T., Tominaga, S. Tissue distribution and subcellular localization of a variant form of the human ST2 gene product, ST2V. Biochem. Biophys. Res. Commun. 285: 1377-1383, 2001. [PubMed: 11478810] [Full Text: https://doi.org/10.1006/bbrc.2001.5306]
Tominaga, S., Inazawa, J., Tsuji, S. Assignment of the human ST2 gene to chromosome 2 at q11.2. Hum. Genet. 97: 561-563, 1996. [PubMed: 8655130] [Full Text: https://doi.org/10.1007/BF02281860]
Tominaga, S., Yokota, T., Yanagisawa, K., Tsukamoto, T., Takagi, T., Tetsuka, T. Nucleotide sequence of a complementary DNA for human ST2. Biochim. Biophys. Acta 1171: 215-218, 1992. [PubMed: 1482686] [Full Text: https://doi.org/10.1016/0167-4781(92)90125-j]
Tominaga, S. A putative protein of a growth specific cDNA from BALB/c-3T3 cells is highly similar to the extracellular portion of mouse interleukin 1 receptor. FEBS Lett. 258: 301-304, 1989. [PubMed: 2532153] [Full Text: https://doi.org/10.1016/0014-5793(89)81679-5]
Tsuzuki, H., Arinobu, Y., Miyawaki, K., Takaki, A., Ota, S., Ota, Y., Mitoma, H., Akahoshi, M., Mori, Y., Iwasaki, H., Niiro, H., Tsukamoto, H., Akashi, K. Functional interleukin-33 receptors are expressed in early progenitor stages of allergy-related granulocytes. Immunology 150: 64-73, 2016. [PubMed: 27568595] [Full Text: https://doi.org/10.1111/imm.12667]
Xu, D., Jiang, H.-R., Kewin, P., Li, Y., Mu, R., Fraser, A. R., Pitman, N., Kurowska-Stolarska, M., McKenzie, A. N. J., McInnes, I. B., Liew, F. Y. IL-33 exacerbates antigen-induced arthritis by activating mast cells. Proc. Nat. Acad. Sci. 105: 10913-10918, 2008. [PubMed: 18667700] [Full Text: https://doi.org/10.1073/pnas.0801898105]
Yagami, A., Orihara, K., Morita, H., Futamura, K., Hashimoto, N., Matsumoto, K., Saito, H., Matsuda, A. IL-33 mediates inflammatory responses in human lung tissue cells. J. Immun. 185: 5743-5750, 2010. [PubMed: 20926795] [Full Text: https://doi.org/10.4049/jimmunol.0903818]