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 40,468,730 bp^[2] End 40,504,575 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in upper lobe of left lung right lung lower lobe of lung left adrenal gland right adrenal gland kidney body of stomach metanephric glomerulus gallbladder sperm Top expressed in duodenum lip ileum jejunum esophagus stomach axial skeleton extraocular muscle rib blastocyst More reference expression data BioGPS More reference expression data
Gene ontology Molecular function interleukin-33 receptor activity interleukin-1 receptor activity cytokine receptor activity protein binding interleukin-33 binding Cellular component integral component of membrane external side of plasma membrane membrane extracellular region plasma 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: 40.47 – 40.5 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 mainly used in intestines, skin or lung epithelial tissues.^[10] Human keratinocytes are expressing this protein just after IFNg stimulation.^[11] Releasing of this cytokine is associated with necrosis or mechanical damage of epithelial or endothelial tissues caused by injury or inflammation. In contrast to related IL-1 cytokines, Il-33 does not need any enzymatic 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 association 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 effector mechanisms trough IL-33/ST2 is present also in TRAF6 deficient mice.^[13]

Even though under IL-33 and IL-1 alarmins relationship, they have different aim to effector function of T regulatory cells. It was shown, that regulatory T cells deficient in IL-1 receptor (IL-1R) have more effective suppression capacity and phenotype stability. It shows, that IL-1 alarmins have an inhibition effect to Tregs.^[14]

There is clear correlation between T regulatory cell ST2 and Th2 specific transcription factor GATA3 expressions. 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 necessary for T regulatory cell phenotype stability and suppression 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 suppressive effect of Tregs is decreased together with ST2 and Foxp3 expression. 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 in their productions are able to cause IBDs.^[15]

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.^[16]

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.^[17]

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". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 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 EK, Xu D, Liu H, Dunne A, McKenzie AN, O'Neill LA, Liew FY (April 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 E (February 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 (April 2012). "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". Journal of Immunology. 188 (7): 3488–95. doi:10.4049/jimmunol.1101977. PMID 22371395.
11. Sundnes O, Pietka W, Loos T, Sponheim J, Rankin AL, Pflanz S, Bertelsen V, Sitek JC, Hol J, Haraldsen G, Khnykin D (July 2015). "Epidermal Expression and Regulation of Interleukin-33 during Homeostasis and Inflammation: Strong Species Differences". The Journal of Investigative Dermatology. 135 (7): 1771–1780. doi:10.1038/jid.2015.85. PMID 25739051.
12. Rehman SU, Mueller T, Januzzi JL (October 2008). "Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure". Journal of the American College of Cardiology. 52 (18): 1458–65. doi:10.1016/j.jacc.2008.07.042. PMID 19017513.
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 (November 2005). "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 (5): 479–490. doi:10.1016/j.immuni.2005.09.015. PMID 16286016.
14. Alvarez F, Istomine R, Shourian M, Pavey N, Al-Aubodah TA, Qureshi S, Fritz JH, Piccirillo CA (May 2019). "The alarmins IL-1 and IL-33 differentially regulate the functional specialisation of Foxp3+ regulatory T cells during mucosal inflammation". Mucosal Immunology. 12 (3): 746–760. doi:10.1038/s41385-019-0153-5. PMID 30872761.
15. Schiering C, Krausgruber T, Chomka A, Fröhlich A, Adelmann K, Wohlfert EA, Pott J, Griseri T, Bollrath J, Hegazy AN, Harrison OJ, Owens BM, Löhning M, Belkaid Y, Fallon PG, Powrie F (September 2014). "The alarmin IL-33 promotes regulatory T-cell function in the intestine". Nature. 513 (7519): 564–568. Bibcode:2014Natur.513..564S. doi:10.1038/nature13577. PMC 4339042. PMID 25043027.
16. Griesenauer B, Paczesny S (2017-04-24). "The ST2/IL-33 Axis in Immune Cells during Inflammatory Diseases". Frontiers in Immunology. 8: 475. doi:10.3389/fimmu.2017.00475. PMC 5402045. PMID 28484466.
17. Pastille E, Wasmer MH, Adamczyk A, Vu VP, Mager LF, Phuong NN, Palmieri V, Simillion C, Hansen W, Kasper S, Schuler M, Muggli B, McCoy KD, Buer J, Zlobec I, Westendorf AM, Krebs P (July 2019). "The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer". Mucosal Immunology. 12 (4): 990–1003. doi:10.1038/s41385-019-0176-y. PMC 7746527. PMID 31165767.

Further reading

• Tominaga S, Yokota T, Yanagisawa K, Tsukamoto T, Takagi T, Tetsuka T (December 1992). "Nucleotide sequence of a complementary DNA for human ST2". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1171 (2): 215–8. doi:10.1016/0167-4781(92)90125-j. PMID 1482686.
• Gayle MA, Slack JL, Bonnert TP, Renshaw BR, Sonoda G, Taguchi T, et al. (March 1996). "Cloning of a putative ligand for the T1/ST2 receptor". The Journal of Biological Chemistry. 271 (10): 5784–9. doi:10.1074/jbc.271.10.5784. PMID 8621446.
• Yanagisawa K, Naito Y, Kuroiwa K, Arai T, Furukawa Y, Tomizuka H, et al. (January 1997). "The expression of ST2 gene in helper T cells and the binding of ST2 protein to myeloma-derived RPMI8226 cells". Journal of Biochemistry. 121 (1): 95–103. doi:10.1093/oxfordjournals.jbchem.a021577. PMID 9058198.
• Kumar S, Tzimas MN, Griswold DE, Young PR (June 1997). "Expression of ST2, an interleukin-1 receptor homologue, is induced by proinflammatory stimuli". Biochemical and Biophysical Research Communications. 235 (3): 474–8. doi:10.1006/bbrc.1997.6810. PMID 9207179.
• Löhning M, Stroehmann A, Coyle AJ, Grogan JL, Lin S, Gutierrez-Ramos JC, et al. (June 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". Proceedings of the National Academy of Sciences of the United States of America. 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 (November 1998). "The IL-1 receptor-related T1 antigen is expressed on immature and mature mast cells and on fetal blood mast cell progenitors". Journal of Immunology. 161 (9): 4866–74. doi:10.4049/jimmunol.161.9.4866. PMID 9794420. S2CID 38887041.
• Saccani S, Polentarutti N, Penton-Rol G, Sims JE, Mantovani A (October 1998). "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 (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.
• Iwahana H, Yanagisawa K, Ito-Kosaka A, Kuroiwa K, Tago K, Komatsu N, et al. (September 1999). "Different promoter usage and multiple transcription initiation sites of the interleukin-1 receptor-related human ST2 gene in UT-7 and TM12 cells". European Journal of Biochemistry. 264 (2): 397–406. doi:10.1046/j.1432-1327.1999.00615.x. PMID 10491084.
• Tominaga S, Kuroiwa K, Tago K, Iwahana H, Yanagisawa K, Komatsu N (October 1999). "Presence and expression of a novel variant form of ST2 gene product in human leukemic cell line UT-7/GM". Biochemical and Biophysical Research Communications. 264 (1): 14–8. doi:10.1006/bbrc.1999.1469. PMID 10527832.
• Li H, Tago K, Io K, Kuroiwa K, Arai T, Iwahana H, et al. (August 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 (November 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Sweet MJ, Leung BP, Kang D, Sogaard M, Schulz K, Trajkovic V, et al. (June 2001). "A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of Toll-like receptor 4 expression". Journal of Immunology. 166 (11): 6633–9. doi:10.4049/jimmunol.166.11.6633. PMID 11359817.
• Tago K, Noda T, Hayakawa M, Iwahana H, Yanagisawa K, Yashiro T, Tominaga S (August 2001). "Tissue distribution and subcellular localization of a variant form of the human ST2 gene product, ST2V". Biochemical and Biophysical Research Communications. 285 (5): 1377–83. doi:10.1006/bbrc.2001.5306. PMID 11478810.
• Lécart S, Lecointe N, Subramaniam A, Alkan S, Ni D, Chen R, et al. (October 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". European Journal of Immunology. 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, Coyle AJ, Gutierrez-Ramos JC, Fallon PG, O'Neill LA (December 2002). "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". The Journal of Biological Chemistry. 277 (51): 49205–11. doi:10.1074/jbc.M209685200. hdl:2262/32919. PMID 12368275.
• Haga Y, Yanagisawa K, Ohto-Ozaki H, Tominaga S, Masuzawa T, Iwahana H (January 2003). "The effect of ST2 gene product on anchorage-independent growth of a glioblastoma cell line, T98G". European Journal of Biochemistry. 270 (1): 163–70. doi:10.1046/j.1432-1033.2003.03377.x. PMID 12492487.
• Weinberg EO, Shimpo M, Hurwitz S, Tominaga S, Rouleau JL, Lee RT (February 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, Van Damme J, Staes A, Thomas GR, Vandekerckhove J (May 2003). "Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides". Nature Biotechnology. 21 (5): 566–9. doi:10.1038/nbt810. PMID 12665801. S2CID 23783563.