Interleukin-13 receptor

The interleukin-13 receptor is a type I cytokine receptor, binding Interleukin-13. It consists of two subunits, encoded by IL13RA1 and IL4R, respectively.^[1][2] These two genes encode the proteins IL-13Rα1 and IL-4Rα. These form a dimer with IL-13 binding to the IL-13Rα1 chain and IL-4Rα stabilises this interaction. This IL-13 receptor can also instigate IL-4 signalling. In both cases this occurs via activation of the Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway, resulting in phosphorylation of STAT6. Phosphorylated STAT6 dimerises and acts as a transcription factor activating many genes, such as eotaxin. ^{[citation needed]}

interleukin 13 receptor, alpha 1
Identifiers
Symbol	IL13RA1
Alt. symbols	IL-13Ra, NR4, CD213a1
NCBI gene	3597
HGNC	5974
OMIM	300119
RefSeq	NM_001560
UniProt	P78552
Other data
Locus	Chr. X q24
Search for Structures Swiss-model Domains InterPro

interleukin 13 receptor, alpha 2
Identifiers
Symbol	IL13RA2
Alt. symbols	IL-13R, IL13BP, CD213a2
NCBI gene	3598
HGNC	5975
OMIM	300130
RefSeq	NM_000640
UniProt	Q14627
Other data
Locus	Chr. X q13.1-q28
Search for Structures Swiss-model Domains InterPro

interleukin 4 receptor
Identifiers
Symbol	IL4R
Alt. symbols	IL4RA; CD124
NCBI gene	3566
HGNC	6015
OMIM	147781
RefSeq	NM_000418
UniProt	Q9H186
Other data
Locus	Chr. 16 p12.1-11.2
Search for Structures Swiss-model Domains InterPro

There is also another receptor that can bind IL-13: IL-13Rα2 encoded by the IL13RA2 gene. This binds IL-13 with very high affinity (and can therefore sequester it) but does not allow IL-4 binding. It acts as a negative regulator of both IL-13 and IL-4, however the mechanism of this is still undetermined.^[3]

Function

Interleukin 13 (IL-13) is an effector cytokine partially sharing the signaling pathways with IL-4 due to the utilization of a common receptor system (IL-4 receptor type II). A “private” receptor system, binding specifically IL-13 with high affinity, seems to use different signalling pathways and is increasingly being studied for its potential as a novel prognostic factor, biomarker or therapeutic target in different types of cancer.^[4][5][6][7]

The “shared” IL-4 / IL-13 receptor

IL-13 uses the IL-4 receptor type II (IL-4RII), a complex formed by an IL-4Rα chain and an IL-13Rα1 chain. Initially, the ligand (IL-4 or IL-13) binds to the IL-4Rα chain and IL-13Rα1 respectively; thereafter, a secondary chain (IL-13Rα1 and IL-4Rα respectively) will also bind, forming the complete IL-4RII. The IL-4/IL-4Rα complex, however, can also bind to a different secondary chain, the IL-2Rγc, forming the IL-4 receptor type I (IL-4RI).^[8] In non-hematopoietic cells, IL-2Rγc is poorly expressed; on the other hand, IL-13Rα1 is poorly expressed in lymphocytes but abundantly in all non-hematopoietic cells; myeloid cells express both of them to a certain degree. This different distribution of secondary chains accounts for the difference in distribution of completed receptors, with being IL-4RI prevalently expressed in lymphocyte, and IL-4RII prevalently in non-hematopoietic cells. Consequently, only IL-4, through IL-4R1, is able to modulate the function of lymphocytes inducing Th2 polarisation and B cells IgG1/IgE class switching, while IL-13 is mainly acting on myeloid cells and non-hematopoietic cells, having strong effects on mucus production, smooth muscle contraction, epithelium permeabilisation (e.g. allergic asthma).^[9] After the complete assemblage, the conformational changes in IL-4RI or IL-4RII tails leads to the intracellular signaling, starting with the auto and cross-phosphorylation of associated Jak kinases (Jak3 for IL-2Rγc, Jak1 for IL-4Rα, Jak2 and Tyk2 for IL-13Rα1),^[10] and followed by phosphorylation of intracellular domains of IL-4Rα in critical Y residues which are therefore activated to form the docking sites for downstream signalling molecules endowed with SH domains.^[8] While the docking sites in IL-4R1 (and consequently IL-4) are able to efficiently activate both STAT6 and IRS2 signalling molecules, IL-4RII (and consequently IL-13) only activates effectively STAT6.^[11] Activated STAT6 molecules form dimers which translocate to the nucleus to bind responsive elements (e.g. CD23 promoter in B cells,^[12] arginase1 enhancer in macrophages^[13] ) The binding affinity of IL-4 for IL-4Rα is much higher than IL-13 for the IL-13Rα1, hence IL-4 would out-compete IL-13 for receptor availability within IL4R2 at parity of concentration.^[14]

The “private” IL-13 receptor

Besides IL-13Rα1 chain (which work in conjunction with the IL-4Rα, IL-13 can bind with much higher affinity to IL-13Rα2. IL-13Rα2 presents 35% homology with IL-13Rα1 and it is expressed mostly in structural cell (but also has been identified in fibroblasts and, only in mice, in soluble form). It presents an extraordinary affinity to IL-13, but does not form complexes with any secondary chain.^[14] Because of the apparent lack of signaling domain and the short tail, it has been initially thought not to have any signaling activity, and regarded as “decoy” receptor, that is its function would just consist in competing for IL-13 binding and neutralizing his effect. Indeed, it has been shown that IL-13Rα2 blocks IL-13 driven STAT6 signalling by binding IL-13 with high affinity, however a partial block is also extending to IL-4 driven STAT6 signalling, presumably due to the cytoplasmic domain interfering with the assembling of IL-4/IL-4Rα with a secondary chain.^[15][16] However, increasing evidences are accumulating that IL-13Rα2 is more than a “decoy”. IL-13 signalling through IL-13Rα2 and AP1-driven TGF-β production has been initially reported in monocytes and then confirmed in mouse models.^[17][18] According these studies, IL-13, through the over-expression (TNF-α induced) of IL-13Rα2 would be able to activate AP-1 signalling and production of TGF-β, driving pro-fibrotic effects. Some recent works is evidencing how a wide range of signals can be actually activated by this receptor (e.g. WNT/β-Catenin, MAPK/ERK, AKT/PKB, Src/FAK, PIP3K ) in normal or pathologic environments. How IL-13Rα2 might overcome the limitation of a 17 aminoacids short tail lacking any signalling motif, it is not clear yet but it has been shown that, at least in some cases, the association with other receptors or signalling adaptors can do the trick.^[19][20]

References

1. Murata T, Obiri NI, Puri RK (March 1998). "Structure of and signal transduction through interleukin-4 and interleukin-13 receptors (review)". International Journal of Molecular Medicine. 1 (3): 551–7. doi:10.3892/ijmm.1.3.551. PMID 9852261.
2. Chomarat P, Banchereau J (1998). "Interleukin-4 and interleukin-13: their similarities and discrepancies". International Reviews of Immunology. 17 (1–4): 1–52. doi:10.3109/08830189809084486. PMID 9914942.
3. Seyfizadeh N, Seyfizadeh N, Gharibi T, Babaloo Z (December 2015). "Interleukin-13 as an important cytokine: A review on its roles in some human diseases" (PDF). Acta Microbiologica et Immunologica Hungarica. 62 (4): 341–78. doi:10.1556/030.62.2015.4.2. PMID 26689873.
4. Thaci B, Brown CE, Binello E, Werbaneth K, Sampath P, Sengupta S (October 2014). "Significance of interleukin-13 receptor alpha 2-targeted glioblastoma therapy". Neuro-Oncology. 16 (10): 1304–12. doi:10.1093/neuonc/nou045. PMC 4165413. PMID 24723564.
5. Suzuki A, Leland P, Joshi BH, Puri RK (September 2015). "Targeting of IL-4 and IL-13 receptors for cancer therapy". Cytokine. 75 (1): 79–88. doi:10.1016/j.cyto.2015.05.026. PMID 26088753.
6. Xie M, Wu XJ, Zhang JJ, He CS (October 2015). "IL-13 receptor α2 is a negative prognostic factor in human lung cancer and stimulates lung cancer growth in mice". Oncotarget. 6 (32): 32902–13. doi:10.18632/oncotarget.5361. PMC 4741738. PMID 26418721.
7. Lin C, Liu H, Zhang H, He H, Li H, Shen Z, Qin J, Qin X, Xu J, Sun Y (August 2016). "Interleukin-13 receptor α2 is associated with poor prognosis in patients with gastric cancer after gastrectomy". Oncotarget. 7 (31): 49281–49288. doi:10.18632/oncotarget.10297. PMC 5226507. PMID 27351230.
8. Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE (1999). "The IL-4 receptor: signaling mechanisms and biologic functions". review. Annual Review of Immunology. 17: 701–38. doi:10.1146/annurev.immunol.17.1.701. PMID 10358772.
9. Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, Donaldson DD (December 1998). "Interleukin-13: central mediator of allergic asthma". primary. Science. 282 (5397): 2258–61. Bibcode:1998Sci...282.2258W. doi:10.1126/science.282.5397.2258. PMID 9856949.
10. Junttila IS (2018). "Tuning the Cytokine Responses: An Update on Interleukin (IL)-4 and IL-13 Receptor Complexes". Frontiers in Immunology. 9: 888. doi:10.3389/fimmu.2018.00888. PMC 6001902. PMID 29930549.
11. Heller NM, Qi X, Junttila IS, Shirey KA, Vogel SN, Paul WE, Keegan AD (December 2008). "Type I IL-4Rs selectively activate IRS-2 to induce target gene expression in macrophages". Science Signaling. 1 (51): ra17. doi:10.1126/scisignal.1164795. PMC 2739727. PMID 19109239.
12. Keegan AD, Conrad DH. The murine lymphocyte receptor for IgE. V. Biosynthesis, transport, and maturation of the B cell Fc epsilon receptor. J Immunol (1987) 139:1199–205
13. Pauleau AL, Rutschman R, Lang R, Pernis A, Watowich SS, Murray PJ (June 2004). "Enhancer-mediated control of macrophage-specific arginase I expression". Journal of Immunology. 172 (12): 7565–73. doi:10.4049/jimmunol.172.12.7565. PMID 15187136.
14. McCormick SM, Heller NM (September 2015). "Commentary: IL-4 and IL-13 receptors and signaling". Cytokine. 75 (1): 38–50. doi:10.1016/j.cyto.2015.05.023. PMC 4546937. PMID 26187331.
15. Chandriani S, DePianto DJ, N'Diaye EN, Abbas AR, Jackman J, Bevers J, et al. (July 2014). "Endogenously expressed IL-13Rα2 attenuates IL-13-mediated responses but does not activate signaling in human lung fibroblasts". Journal of Immunology. 193 (1): 111–9. doi:10.4049/jimmunol.1301761. PMID 24879793.
16. Zheng T, Liu W, Oh SY, Zhu Z, Hu B, Homer RJ, Cohn L, Grusby MJ, Elias JA (January 2008). "IL-13 receptor alpha2 selectively inhibits IL-13-induced responses in the murine lung". Journal of Immunology. 180 (1): 522–9. doi:10.4049/jimmunol.180.1.522. PMID 18097054.
17. Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A (January 2006). "IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis". Nature Medicine. 12 (1): 99–106. doi:10.1038/nm1332. PMID 16327802. S2CID 38397076.
18. Brunner SM, Schiechl G, Kesselring R, Martin M, Balam S, Schlitt HJ, Geissler EK, Fichtner-Feigl S (October 2013). "IL-13 signaling via IL-13Rα2 triggers TGF-β1-dependent allograft fibrosis". Transplantation Research. 2 (1): 16. doi:10.1186/2047-1440-2-16. PMC 4016099. PMID 24143891.
19. Bartolomé RA, García-Palmero I, Torres S, López-Lucendo M, Balyasnikova IV, Casal JI (June 2015). "IL13 Receptor α2 Signaling Requires a Scaffold Protein, FAM120A, to Activate the FAK and PI3K Pathways in Colon Cancer Metastasis". Cancer Research. 75 (12): 2434–44. doi:10.1158/0008-5472.CAN-14-3650. hdl:10261/123035. PMID 25896327.
20. He CH, Lee CG, Dela Cruz CS, Lee CM, Zhou Y, Ahangari F, Ma B, Herzog EL, Rosenberg SA, Li Y, Nour AM, Parikh CR, Schmidt I, Modis Y, Cantley L, Elias JA (August 2013). "Chitinase 3-like 1 regulates cellular and tissue responses via IL-13 receptor α2". Cell Reports. 4 (4): 830–41. doi:10.1016/j.celrep.2013.07.032. PMC 3988532. PMID 23972995.

External links

• Receptors,+Interleukin-13 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)