IL1RL1
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]
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).
Clinical significance
ST2 is a novel biomarker of cardiac stress. ST2 signals the presence and severity of adverse cardiac remodeling and tissue [fibrosis]], which occurs in response to myocardial infarction, acute coronary syndrome, or worsening heart failure.[4][5]
Published and peer-reviewed evidence continues to confirm that ST2 is a powerful predictor of mortality at presentation.[6] Studies have shown patients with ST2 levels above a clinical threshold consistently have a much higher risk of mortality while, equally important, patients with ST2 levels below threshold have a very low risk of mortality.[7] There is no level that perfectly separates patients with and without heart failure. However there is shown to be a higher risk of adverse outcomes when ST2 level is above a cutoff value of 35ng/mL.[7]
Mutations in this gene have been linked to atopic dermatitis and asthma.
ST2 cardiac biomarker
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). 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 counter-balanced 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.
Clinical utility
- ST2 has considerable prognostic value and is used as an aid for risk stratification in identifying patients who are at high risk of mortality and rehospitalization in patients diagnosed with heart failure.[8]
- ST2 is independent of natriuretic peptides, such as natriuretic peptide BNP and NT-proBNP, and therefore provide unique and complementary prognostic information.[9]
- ST2 is also not adversely influenced by age, impaired renal function or elevated body mass index (BMI), common confounding situations for natriuretic peptide measurements.[5]
- Repeated measurements of ST2 may aid in clinical decision-making.[8]
The ST2 Test
ST2 is measured by immunoassay. The Presage ST2 Assay is the only test that quantitatively measures the level of ST2 in blood. The Presage ST2 Assay is offered exclusively by Critical Diagnostics of San Diego, California. [10] Critical Diagnostics has US Food and Drug Administration FDA 510(k) approval and has CE Mark for the manufacture and sale of The Presage ST2 Assay. [10]
References
- ^ "Entrez Gene: IL1RL1 interleukin 1 receptor-like 1". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9173.
- ^ 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. PMID 1482686.
- ^ 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.
- ^ Shah RV, Januzzi JL (March 2010). "ST2: a novel remodeling biomarker in acute and chronic heart failure". Curr Heart Fail Rep 7 (1): 9–14. doi:10.1007/s11897-010-0005-9. PMID 20425491.
- ^ a b Rehman SU, Mueller T, Januzzi JL (October 2008). "Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure". J. Am. Coll. Cardiol. 52 (18): 1458–65. doi:10.1016/j.jacc.2008.07.042. PMID 19017513.
- ^ Braunwald E (May 2008). "Biomarkers in heart failure". N. Engl. J. Med. 358 (20): 2148–59. doi:10.1056/NEJMra0800239. PMID 18480207.
- ^ a b Kohli P, Bonaca MP, Kakkar R, Kudinova AY, Scirica BM, Sabatine MS, Murphy SA, Braunwald E, Lee RT, Morrow DA (November 2011). "Role of ST2 in Non-ST-Elevation Acute Coronary Syndrome in the MERLIN-TIMI 36 Trial". Clin. Chem.. doi:10.1373/clinchem.2011.173369. PMID 22096031.
- ^ a b Bayes-Genis A, Pascual-Figal D, Januzzi JL, Maisel A, Casas T, Valdés Chávarri M, Ordóñez-Llanos J (October 2010). "Soluble ST2 monitoring provides additional risk stratification for outpatients with decompensated heart failure". Rev Esp Cardiol 63 (10): 1171–8. PMID 20875357.
- ^ Sabatine MS, Morrow DA, Higgins LJ, MacGillivray C, Guo W, Bode C, Rifai N, Cannon CP, Gerszten RE, Lee RT (April 2008). "Complementary roles for biomarkers of biomechanical strain ST2 and N-terminal prohormone B-type natriuretic peptide in patients with ST-elevation myocardial infarction". Circulation 117 (15): 1936–44. doi:10.1161/CIRCULATIONAHA.107.728022. PMID 18378613.
- ^ a b [1],
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. 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. 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. doi:10.1073/pnas.95.12.6930. PMC 22690. PMID 9618516. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=22690.
- 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=310948.
- 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. 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. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241.
- 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.