IL1RL1

Interleukin 1 receptor-like 1, also known as IL1RL1 and ST2, is a protein that in humans is encoded by the IL1RL1 gene.[5][6][7]

IL1RL1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4KC3
Identifiers
Aliases	IL1RL1, DER4, FIT-1, IL33R, ST2, ST2L, ST2V, T1, interleukin 1 receptor like 1
External IDs	OMIM: 601203 MGI: 98427 HomoloGene: 2862 GeneCards: IL1RL1
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q12.1 Start 102,311,502 bp[1] End 102,352,037 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1 B|1 19.19 cM Start 40,429,570 bp[2] End 40,465,415 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • interleukin-33 receptor activity • interleukin-1 receptor activity • cytokine receptor activity • GO:0001948 protein binding • interleukin-33 binding Cellular component • integral component of membrane • external side of plasma membrane • membrane • extracellular region • cell membrane • extracellular matrix Biological process • negative regulation of T-helper 1 type immune response • positive regulation of inflammatory response • negative regulation of interferon-gamma production • positive regulation of macrophage activation • negative regulation of I-kappaB kinase/NF-kappaB signaling • signal transduction • immune response • positive regulation of interleukin-5 production • interleukin-33-mediated signaling pathway Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	9173	17082
Ensembl	ENSG00000115602	ENSMUSG00000026069
UniProt	Q01638	P14719
RefSeq (mRNA)	NM_001282408 NM_003856 NM_016232 NM_173459	NM_001025602 NM_001294171 NM_010743
RefSeq (protein)	NP_001269337 NP_003847 NP_057316	NP_001020773 NP_001281100 NP_034873
Location (UCSC)	Chr 2: 102.31 – 102.35 Mb	Chr 1: 40.43 – 40.47 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

IL1RL1 is a member of the Toll-like receptor superfamily based on the function of its intracellular TIR domain, but its extracellular region is composed of immunoglobulin domains. Unlike other members of the family IL1RL1 does not induce an inflammatory response through activation of NF-κB, although it does activate MAP kinases.[8]

ST2 is a member of the interleukin 1 receptor family. The ST2 protein has two isoforms and is directly implicated in the progression of cardiac disease: a soluble form (referred to as soluble ST2 or sST2) and a membrane-bound receptor form (referred to as the ST2 receptor or ST2L). When the myocardium is stretched, the ST2 gene is upregulated, increasing the concentration of circulating soluble ST2.[9] The ligand for ST2 is the cytokine Interleukin-33(IL-33). Binding of IL-33 to the ST2 receptor, in response to cardiac disease or injury, such as an ischemic event, elicits a cardioprotective effect resulting in preserved cardiac function. This cardioprotective IL-33 signal is counterbalanced by the level of soluble ST2, which binds IL-33 and makes it unavailable to the ST2 receptor for cardioprotective signaling. As a result, the heart is subjected to greater stress in the presence of high levels of soluble ST2.

Molecular biology

The gene is found on the long arm of Chromosome 2 (2q12). It is 40,536 bases long and is located on the Watson (plus) strand. It encodes a protein of 556 amino acids (molecular weight 63,358 Da). Both membrane bound and soluble forms are known. The protein is known to interact with MyD88, IRAK1, IRAK4 and TRAF6. It appears to be essential for the normal function of T helper cells type 2 (Th2 cells) .

Regulatory T cells

Alarmin IL-33 is constitutively expressed as a nuclear protein in all epithelial and endothelial cells, but also in secondary lymphoid organs. The biological and immunological function of this cytokine is even thouhg mainly used in intestines, skin or lung epithelial tissues.[10] Human keratinocytes are expresing this protein just after IFNg stimulation[11].Releasig of this cytokine is asociated with necrosis or mechanical damage of epithelial or endothelial tissues caused by injury or inflamation. In contrast to related IL-1 cytokines, Il-33 does not need any enzymtic cleavage for activation and its function.

Two isoforms of ST2 were described in mammals. The membrane-bound ST2, which provides the activation pathway and soluble ST2 that originates from another promoter region of the il1rl1 gene and lacks the transmembrane and cytoplasmic domains.[12] Interestingly, all the members of the IL-1 family such as receptor share a common intracellular Toll/IL-1 receptor (TIR) domain. IL-33 binds specifically to ST2, which in asociation with IL1RAcP to form a heterodimeric receptor and TIR domain dimerization together with MyD88 leads to activation of TRAF6. This signal transduction is not crucial. Activation of cell efector mechanisms trough IL-33/ST2 is present also in TRAF6 deficient mice.[13]

Even though under IL-33 and IL-1 alarmins relationship, tney have different aim to efector function of T regulatory cells. It was shown, that regulatory T cells deficient in IL-1 receptor (IL-1R) have more efective supresion capacity and phenotype stability. It shows, that IL-1 alarmins have inhibiton efect to Tregs.[14]

There is clear correlation betwen T regulatory cell ST2 and Th2 specific transcription factor GATA3 expresions. The both molecules are present in T regulatory cells together. GATA3 transcription factor has been shown to promote ST2 gene expression by binding to an enhancer element of foxp3 gene. Foxp3 transcription factor is necesary for T regulatory cell phenotype stability and supresion function mainly based on gene silence effect. It was also shown, that after different cytokine IL-23 stimulation which leads to activation of STAT3, the supressive effect of Tregs is decreased together with ST2 and Foxp3 expresion. It looks, that GATA3 with presence of STAT3 has different preferences in gene expression regulation.[15] This observation suggest longterm theory about crucial role on antagonistic aims of IL-33 and IL-23 to mucosal immunity and disbalantions in their productions are able to cause severe IBDs.

In ST2+ T Regulatory cell is present soluble form of ST2 without transmembrane and cytosolic domain. After IL-33 signalization through membrane ST2 in Tregs indicates expression of both membrane and soluble isoforms. Releasing of soluble ST2 into extracellular space cause neutralization of IL-33 and regulation of inflammation mainly caused by Th17 cells, which also express ST2.

Cancer

It is well known, that high presence of T regulatory cells in cancer immune reaction do not mean good prognosis for oncologic patients. It was observed, that depletion of ST2 or IL-33 in colon or intestine cancer makes higher development of Th1 immune reaction with presence of CD8+ cytotoxic T cells, which are the most efficient in cancer treatment.[16]

Clinical significance

Mutations in this gene have been linked to atopic dermatitis and asthma.

The protein encoded by this gene serves as a cardiac biomarker.

References

1. GRCh38: Ensembl release 89: ENSG00000115602 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000026069 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: IL1RL1 interleukin 1 receptor-like 1".
6. Tominaga S, Yokota T, Yanagisawa K, Tsukamoto T, Takagi T, Tetsuka T (December 1992). "Nucleotide sequence of a complementary DNA for human ST2". Biochim. Biophys. Acta. 1171 (2): 215–8. doi:10.1016/0167-4781(92)90125-j. PMID 1482686.
7. Dale M, Nicklin MJ (April 1999). "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 (1): 177–9. doi:10.1006/geno.1999.5767. PMID 10191101.
8. Brint, Elizabeth K; Xu, Damo; Liu, Haiying; Dunne, Aisling; McKenzie, Andrew N J; O'Neill, Luke A J; Liew, Foo Y (2004). "ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance". Nature Immunology. 5 (4): 373–9. doi:10.1038/ni1050. PMID 15004556. S2CID 29364769.
9. Braunwald, Eugene (2013). "Heart Failure". JACC: Heart Failure. 1 (1): 1–20. doi:10.1016/j.jchf.2012.10.002. PMID 24621794.
10. "Pichery M, Mirey E, Mercier P, Lefrancais E, Dujardin A, Ortega N, Girard JP. Endogenous IL-33 is highly expressed in mouse epithelial barrier tissues, lymphoid organs, brain, embryos, and inflamed tissues: in situ analysis using a novel Il-33-LacZ gene trap reporter strain. J Immunol. 2012 Apr 1;188(7):3488-95. doi: 10.4049/jimmunol.1101977. Epub 2012 Feb 27. PMID: 22371395". Cite journal requires |journal= (help)
11. "Sundnes O, Pietka W, Loos T, Sponheim J, Rankin AL, Pflanz S, Bertelsen V, Sitek JC, Hol J, Haraldsen G, Khnykin D. Epidermal Expression and Regulation of Interleukin-33 during Homeostasis and Inflammation: Strong Species Differences. J Invest Dermatol. 2015 Jul;135(7):1771-1780. doi: 10.1038/jid.2015.85. Epub 2015 Mar 4. PMID: 25739051". Cite journal requires |journal= (help)
12. "Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure". Cite journal requires |journal= (help)
13. "Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA. 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. 2005 Nov;23(5):479-90. doi: 10.1016/j.immuni.2005.09.015. PMID: 16286016". Cite journal requires |journal= (help)
14. "Alvarez F, Istomine R, Shourian M, Pavey N, Al-Aubodah TA, Qureshi S, Fritz JH, Piccirillo CA. The alarmins IL-1 and IL-33 differentially regulate the functional specialisation of Foxp3+ regulatory T cells during mucosal inflammation. Mucosal Immunol. 2019 May;12(3):746-760. doi: 10.1038/s41385-019-0153-5. Epub 2019 Mar 11. PMID: 30872761". Cite journal requires |journal= (help)
15. Schiering C, Krausgruber T, Chomka A, Fröhlich A, Adelmann K, Wohlfert EA, Pott J, Griseri T, Bollrath J, Hegazy AN, Harrison OJ, Owens BMJ, Löhning M, Belkaid Y, Fallon PG, Powrie F. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature. 2014 Sep 25;513(7519):564-568. doi: 10.1038/nature13577. Epub 2014 Jul 16. PMID: 25043027; PMCID: PMC4339042.
16. "Pastille E, Wasmer MH, Adamczyk A, Vu VP, Mager LF, Phuong NNT, Palmieri V, Simillion C, Hansen W, Kasper S, Schuler M, Muggli B, McCoy KD, Buer J, Zlobec I, Westendorf AM, Krebs P. The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer. Mucosal Immunol. 2019 Jul;12(4):990-1003. doi: 10.1038/s41385-019-0176-y. Epub 2019 Jun 5. PMID: 31165767; PMCID: PMC7746527". Cite journal requires |journal= (help)

Further reading

• Tominaga S, Yokota T, Yanagisawa K, et al. (1993). "Nucleotide sequence of a complementary DNA for human ST2". Biochim. Biophys. Acta. 1171 (2): 215–8. doi:10.1016/0167-4781(92)90125-j. PMID 1482686.
• Gayle MA, Slack JL, Bonnert TP, et al. (1996). "Cloning of a putative ligand for the T1/ST2 receptor". J. Biol. Chem. 271 (10): 5784–9. doi:10.1074/jbc.271.10.5784. PMID 8621446.
• Yanagisawa K, Naito Y, Kuroiwa K, et al. (1997). "The expression of ST2 gene in helper T cells and the binding of ST2 protein to myeloma-derived RPMI8226 cells". J. Biochem. 121 (1): 95–103. doi:10.1093/oxfordjournals.jbchem.a021577. PMID 9058198.
• Kumar S, Tzimas MN, Griswold DE, Young PR (1997). "Expression of ST2, an interleukin-1 receptor homologue, is induced by proinflammatory stimuli". Biochem. Biophys. Res. Commun. 235 (3): 474–8. doi:10.1006/bbrc.1997.6810. PMID 9207179.
• Löhning M, Stroehmann A, Coyle AJ, et al. (1998). "T1/ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function". Proc. Natl. Acad. Sci. U.S.A. 95 (12): 6930–5. Bibcode:1998PNAS...95.6930L. doi:10.1073/pnas.95.12.6930. PMC 22690. PMID 9618516.
• Moritz DR, Rodewald HR, Gheyselinck J, Klemenz R (1998). "The IL-1 receptor-related T1 antigen is expressed on immature and mature mast cells and on fetal blood mast cell progenitors". J. Immunol. 161 (9): 4866–74. PMID 9794420.
• Saccani S, Polentarutti N, Penton-Rol G, et al. (1999). "Divergent effects of LPS on expression of IL-1 receptor family members in mononuclear phagocytes in vitro and in vivo". Cytokine. 10 (10): 773–80. doi:10.1006/cyto.1998.0359. PMID 9811530.
• Dale M, Nicklin MJ (1999). "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 (1): 177–9. doi:10.1006/geno.1999.5767. PMID 10191101.
• Iwahana H, Yanagisawa K, Ito-Kosaka A, et al. (1999). "Different promoter usage and multiple transcription initiation sites of the interleukin-1 receptor-related human ST2 gene in UT-7 and TM12 cells". Eur. J. Biochem. 264 (2): 397–406. doi:10.1046/j.1432-1327.1999.00615.x. PMID 10491084.
• Tominaga S, Kuroiwa K, Tago K, et al. (1999). "Presence and expression of a novel variant form of ST2 gene product in human leukemic cell line UT-7/GM". Biochem. Biophys. Res. Commun. 264 (1): 14–8. doi:10.1006/bbrc.1999.1469. PMID 10527832.
• Li H, Tago K, Io K, et al. (2000). "The cloning and nucleotide sequence of human ST2L cDNA". Genomics. 67 (3): 284–90. doi:10.1006/geno.2000.6269. PMID 10936050.
• Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Sweet MJ, Leung BP, Kang D, et al. (2001). "A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of Toll-like receptor 4 expression". J. Immunol. 166 (11): 6633–9. doi:10.4049/jimmunol.166.11.6633. PMID 11359817.
• Tago K, Noda T, Hayakawa M, et al. (2001). "Tissue distribution and subcellular localization of a variant form of the human ST2 gene product, ST2V". Biochem. Biophys. Res. Commun. 285 (5): 1377–83. doi:10.1006/bbrc.2001.5306. PMID 11478810.
• Lécart S, Lecointe N, Subramaniam A, et al. (2002). "Activated, but not resting human Th2 cells, in contrast to Th1 and T regulatory cells, produce soluble ST2 and express low levels of ST2L at the cell surface". Eur. J. Immunol. 32 (10): 2979–87. doi:10.1002/1521-4141(2002010)32:10<2979::AID-IMMU2979>3.0.CO;2-5. PMID 12355452.
• Brint EK, Fitzgerald KA, Smith P, et al. (2003). "Characterization of signaling pathways activated by the interleukin 1 (IL-1) receptor homologue T1/ST2. A role for Jun N-terminal kinase in IL-4 induction". J. Biol. Chem. 277 (51): 49205–11. doi:10.1074/jbc.M209685200. PMID 12368275.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Haga Y, Yanagisawa K, Ohto-Ozaki H, et al. (2003). "The effect of ST2 gene product on anchorage-independent growth of a glioblastoma cell line, T98G". Eur. J. Biochem. 270 (1): 163–70. doi:10.1046/j.1432-1033.2003.03377.x. PMID 12492487.
• Weinberg EO, Shimpo M, Hurwitz S, et al. (2003). "Identification of serum soluble ST2 receptor as a novel heart failure biomarker". Circulation. 107 (5): 721–6. doi:10.1161/01.CIR.0000047274.66749.FE. PMID 12578875.
• Gevaert K, Goethals M, Martens L, et al. (2004). "Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides". Nat. Biotechnol. 21 (5): 566–9. doi:10.1038/nbt810. PMID 12665801. S2CID 23783563.