IL1RL1 is a member of the Toll-like receptor superfamily based on the function of its intracelluar 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.
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. 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.
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) .
^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. PMID1482686.
^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. PMID10191101.
^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". Nat. Immunol. 5 (4): 373–9. doi:10.1038/ni1050. PMID15004556.
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. PMID9207179.
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. PMID9794420.
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. PMID9811530.
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. PMID10191101.
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. PMID10491084.
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. PMID10527832.
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. PMID11359817.
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. PMID11478810.
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. PMID12368275.
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. PMID12492487.
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. PMID12665801.