IL1RL1 explained

Interleukin 1 receptor-like 1, also known as IL1RL1 and ST2, is a protein that in humans is encoded by the IL1RL1 gene.^{[1] [2] [3]}

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.^[4]

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.^[5] 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.^[6] Human keratinocytes are expressing this protein just after IFNg stimulation.^[7] 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.^[8] 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.^[9]

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.^[10]

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.^[11] 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.

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.^[12]

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.^[13]

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.

Further reading

• Tominaga S, Yokota T, Yanagisawa K, Tsukamoto T, Takagi T, Tetsuka T . Nucleotide sequence of a complementary DNA for human ST2 . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1171 . 2 . 215–8 . December 1992 . 1482686 . 10.1016/0167-4781(92)90125-j .
• Gayle MA, Slack JL, Bonnert TP, Renshaw BR, Sonoda G, Taguchi T, Testa JR, Dower SK, Sims JE . 6 . Cloning of a putative ligand for the T1/ST2 receptor . The Journal of Biological Chemistry . 271 . 10 . 5784–9 . March 1996 . 8621446 . 10.1074/jbc.271.10.5784 . free .
• Yanagisawa K, Naito Y, Kuroiwa K, Arai T, Furukawa Y, Tomizuka H, Miura Y, Kasahara T, Tetsuka T, Tominaga S . 6 . 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 . January 1997 . 9058198 . 10.1093/oxfordjournals.jbchem.a021577 .
• Kumar S, Tzimas MN, Griswold DE, Young PR . Expression of ST2, an interleukin-1 receptor homologue, is induced by proinflammatory stimuli . Biochemical and Biophysical Research Communications . 235 . 3 . 474–8 . June 1997 . 9207179 . 10.1006/bbrc.1997.6810 .
• Löhning M, Stroehmann A, Coyle AJ, Grogan JL, Lin S, Gutierrez-Ramos JC, Levinson D, Radbruch A, Kamradt T . 6 . 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 . June 1998 . 9618516 . 22690 . 10.1073/pnas.95.12.6930 . 1998PNAS...95.6930L . free .
• Moritz DR, Rodewald HR, Gheyselinck J, Klemenz R . 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 . November 1998 . 10.4049/jimmunol.161.9.4866 . 9794420 . 38887041 . free .
• Saccani S, Polentarutti N, Penton-Rol G, Sims JE, Mantovani A . 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 . October 1998 . 9811530 . 10.1006/cyto.1998.0359 .
• Dale M, Nicklin MJ . 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 . April 1999 . 10191101 . 10.1006/geno.1999.5767 .
• Iwahana H, Yanagisawa K, Ito-Kosaka A, Kuroiwa K, Tago K, Komatsu N, Katashima R, Itakura M, Tominaga S . 6 . 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 . September 1999 . 10491084 . 10.1046/j.1432-1327.1999.00615.x .
• Tominaga S, Kuroiwa K, Tago K, Iwahana H, Yanagisawa K, Komatsu N . 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 . October 1999 . 10527832 . 10.1006/bbrc.1999.1469 .
• Li H, Tago K, Io K, Kuroiwa K, Arai T, Iwahana H, Tominaga S, Yanagisawa K . 6 . The cloning and nucleotide sequence of human ST2L cDNA . Genomics . 67 . 3 . 284–90 . August 2000 . 10936050 . 10.1006/geno.2000.6269 .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Sweet MJ, Leung BP, Kang D, Sogaard M, Schulz K, Trajkovic V, Campbell CC, Xu D, Liew FY . 6 . 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 . June 2001 . 11359817 . 10.4049/jimmunol.166.11.6633 . free .
• 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 . Biochemical and Biophysical Research Communications . 285 . 5 . 1377–83 . August 2001 . 11478810 . 10.1006/bbrc.2001.5306 .
• Lécart S, Lecointe N, Subramaniam A, Alkan S, Ni D, Chen R, Boulay V, Pène J, Kuroiwa K, Tominaga S, Yssel H . 6 . 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 . October 2002 . 12355452 . 10.1002/1521-4141(2002010)32:10<2979::AID-IMMU2979>3.0.CO;2-5 . free .
• Brint EK, Fitzgerald KA, Smith P, Coyle AJ, Gutierrez-Ramos JC, Fallon PG, O'Neill LA . 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 . December 2002 . 12368275 . 10.1074/jbc.M209685200 . free . 2262/32919 . free .
• Haga Y, Yanagisawa K, Ohto-Ozaki H, Tominaga S, Masuzawa T, Iwahana H . The effect of ST2 gene product on anchorage-independent growth of a glioblastoma cell line, T98G . European Journal of Biochemistry . 270 . 1 . 163–70 . January 2003 . 12492487 . 10.1046/j.1432-1033.2003.03377.x . free .
• Weinberg EO, Shimpo M, Hurwitz S, Tominaga S, Rouleau JL, Lee RT . Identification of serum soluble ST2 receptor as a novel heart failure biomarker . Circulation . 107 . 5 . 721–6 . February 2003 . 12578875 . 10.1161/01.CIR.0000047274.66749.FE . free .
• Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J . Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides . Nature Biotechnology . 21 . 5 . 566–9 . May 2003 . 12665801 . 10.1038/nbt810 . 23783563 .

Notes and References

1. Web site: Entrez Gene: IL1RL1 interleukin 1 receptor-like 1.
2. Tominaga S, Yokota T, Yanagisawa K, Tsukamoto T, Takagi T, Tetsuka T . Nucleotide sequence of a complementary DNA for human ST2 . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1171 . 2 . 215–8 . December 1992 . 1482686 . 10.1016/0167-4781(92)90125-j .
3. Dale M, Nicklin MJ . 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 . April 1999 . 10191101 . 10.1006/geno.1999.5767 .
4. Brint EK, Xu D, Liu H, Dunne A, McKenzie AN, O'Neill LA, Liew FY . ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance . Nature Immunology . 5 . 4 . 373–9 . April 2004 . 15004556 . 10.1038/ni1050 . 29364769 . Luke A. J. O'Neill . Andrew N. J. McKenzie .
5. Braunwald E . Heart failure . JACC. Heart Failure . 1 . 1 . 1–20 . February 2013 . 24621794 . 10.1016/j.jchf.2012.10.002 . free .
6. 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 . Journal of Immunology . 188 . 7 . 3488–95 . April 2012 . 22371395 . 10.4049/jimmunol.1101977 . free .
7. 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 . The Journal of Investigative Dermatology . 135 . 7 . 1771–1780 . July 2015 . 25739051 . 10.1038/jid.2015.85 . free .
8. Rehman SU, Mueller T, Januzzi JL . 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 . October 2008 . 19017513 . 10.1016/j.jacc.2008.07.042 . free .
9. 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 . November 2005 . 23 . 5 . 479–490 . 10.1016/j.immuni.2005.09.015 . 16286016. free .
10. 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 Immunology . 12 . 3 . 746–760 . May 2019 . 30872761 . 10.1038/s41385-019-0153-5 . free .
11. 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 . The alarmin IL-33 promotes regulatory T-cell function in the intestine . Nature . 513 . 7519 . 564–568 . September 2014 . 25043027 . 4339042 . 10.1038/nature13577 . 2014Natur.513..564S .
12. Griesenauer B, Paczesny S . The ST2/IL-33 Axis in Immune Cells during Inflammatory Diseases . Frontiers in Immunology . 8 . 475 . 2017-04-24 . 28484466 . 5402045 . 10.3389/fimmu.2017.00475 . free .
13. 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 . The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer . Mucosal Immunology . 12 . 4 . 990–1003 . July 2019 . 31165767 . 7746527 . 10.1038/s41385-019-0176-y .