IL1RL1

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IL1RL1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesIL1RL1, DER4, FIT-1, IL33R, ST2, ST2L, ST2V, T1, interleukin 1 receptor like 1
External IDsOMIM: 601203 MGI: 98427 HomoloGene: 2862 GeneCards: IL1RL1
Orthologs
SpeciesHumanMouse
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 MbChr 1: 40.47 – 40.5 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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]

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. ^ a b c GRCh38: Ensembl release 89: ENSG00000115602 – Ensembl, May 2017
  2. ^ a b c 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. ^ a b 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

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