Interleukin-13 receptor

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.{{cite journal | vauthors = Thaci B, Brown CE, Binello E, Werbaneth K, Sampath P, Sengupta S | title = Significance of interleukin-13 receptor alpha 2-targeted glioblastoma therapy | journal = Neuro-Oncology | volume = 16 | issue = 10 | pages = 1304–12 | date = October 2014 | pmid = 24723564 | pmc = 4165413 | doi = 10.1093/neuonc/nou045 }}{{cite journal | vauthors = Suzuki A, Leland P, Joshi BH, Puri RK | title = Targeting of IL-4 and IL-13 receptors for cancer therapy | journal = Cytokine | volume = 75 | issue = 1 | pages = 79–88 | date = September 2015 | pmid = 26088753 | doi = 10.1016/j.cyto.2015.05.026 }}{{cite journal | vauthors = Xie M, Wu XJ, Zhang JJ, He CS | title = IL-13 receptor α2 is a negative prognostic factor in human lung cancer and stimulates lung cancer growth in mice | journal = Oncotarget | volume = 6 | issue = 32 | pages = 32902–13 | date = October 2015 | pmid = 26418721 | pmc = 4741738 | doi = 10.18632/oncotarget.5361 }}{{cite journal | vauthors = Lin C, Liu H, Zhang H, He H, Li H, Shen Z, Qin J, Qin X, Xu J, Sun Y | title = Interleukin-13 receptor α2 is associated with poor prognosis in patients with gastric cancer after gastrectomy | journal = Oncotarget | volume = 7 | issue = 31 | pages = 49281–49288 | date = August 2016 | pmid = 27351230 | pmc = 5226507 | doi = 10.18632/oncotarget.10297 }}

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).{{cite journal | vauthors = Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE | title = The IL-4 receptor: signaling mechanisms and biologic functions | journal = Annual Review of Immunology | volume = 17 | pages = 701–38 | date = 1999 | pmid = 10358772 | doi = 10.1146/annurev.immunol.17.1.701 | department = review | url = https://zenodo.org/record/1234989 }} 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).{{cite journal | vauthors = Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, Donaldson DD | title = Interleukin-13: central mediator of allergic asthma | journal = Science | volume = 282 | issue = 5397 | pages = 2258–61 | date = December 1998 | pmid = 9856949 | doi = 10.1126/science.282.5397.2258| bibcode = 1998Sci...282.2258W | department = primary | doi-access = free }}

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),{{cite journal | vauthors = Junttila IS | title = Tuning the Cytokine Responses: An Update on Interleukin (IL)-4 and IL-13 Receptor Complexes | journal = Frontiers in Immunology | volume = 9 | pages = 888 | date = 2018 | pmid = 29930549 | pmc = 6001902 | doi = 10.3389/fimmu.2018.00888 | doi-access = free }} 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. 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.{{cite journal | vauthors = Heller NM, Qi X, Junttila IS, Shirey KA, Vogel SN, Paul WE, Keegan AD | title = Type I IL-4Rs selectively activate IRS-2 to induce target gene expression in macrophages | journal = Science Signaling | volume = 1 | issue = 51 | pages = ra17 | date = December 2008 | pmid = 19109239 | pmc = 2739727 | doi = 10.1126/scisignal.1164795 }} Activated STAT6 molecules form dimers which translocate to the nucleus to bind responsive elements (e.g. CD23 promoter in B cells,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 arginase1 enhancer in macrophages{{cite journal | vauthors = Pauleau AL, Rutschman R, Lang R, Pernis A, Watowich SS, Murray PJ | title = Enhancer-mediated control of macrophage-specific arginase I expression | journal = Journal of Immunology | volume = 172 | issue = 12 | pages = 7565–73 | date = June 2004 | pmid = 15187136 | doi = 10.4049/jimmunol.172.12.7565| doi-access = free }} )

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.{{cite journal | vauthors = McCormick SM, Heller NM | title = Commentary: IL-4 and IL-13 receptors and signaling | journal = Cytokine | volume = 75 | issue = 1 | pages = 38–50 | date = September 2015 | pmid = 26187331 | pmc = 4546937 | doi = 10.1016/j.cyto.2015.05.023 }}

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.

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.{{cite journal | vauthors = Chandriani S, DePianto DJ, N'Diaye EN, Abbas AR, Jackman J, Bevers J, Ramirez-Carrozzi V, Pappu R, Kauder SE, Toy K, Ha C, Modrusan Z, Wu LC, Collard HR, Wolters PJ, Egen JG, Arron JR | display-authors = 6 | title = Endogenously expressed IL-13Rα2 attenuates IL-13-mediated responses but does not activate signaling in human lung fibroblasts | journal = Journal of Immunology | volume = 193 | issue = 1 | pages = 111–9 | date = July 2014 | pmid = 24879793 | doi = 10.4049/jimmunol.1301761 | doi-access = free }}{{cite journal | vauthors = Zheng T, Liu W, Oh SY, Zhu Z, Hu B, Homer RJ, Cohn L, Grusby MJ, Elias JA | title = IL-13 receptor alpha2 selectively inhibits IL-13-induced responses in the murine lung | journal = Journal of Immunology | volume = 180 | issue = 1 | pages = 522–9 | date = January 2008 | pmid = 18097054 | doi = 10.4049/jimmunol.180.1.522| doi-access = free }}

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.{{cite journal | vauthors = Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A | title = IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis | journal = Nature Medicine | volume = 12 | issue = 1 | pages = 99–106 | date = January 2006 | pmid = 16327802 | doi = 10.1038/nm1332 | s2cid = 38397076 }}{{cite journal | vauthors = Brunner SM, Schiechl G, Kesselring R, Martin M, Balam S, Schlitt HJ, Geissler EK, Fichtner-Feigl S | title = IL-13 signaling via IL-13Rα2 triggers TGF-β1-dependent allograft fibrosis | journal = Transplantation Research | volume = 2 | issue = 1 | pages = 16 | date = October 2013 | pmid = 24143891 | pmc = 4016099 | doi = 10.1186/2047-1440-2-16 | doi-access = free }} 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.{{cite journal | vauthors = Bartolomé RA, García-Palmero I, Torres S, López-Lucendo M, Balyasnikova IV, Casal JI | title = IL13 Receptor α2 Signaling Requires a Scaffold Protein, FAM120A, to Activate the FAK and PI3K Pathways in Colon Cancer Metastasis | journal = Cancer Research | volume = 75 | issue = 12 | pages = 2434–44 | date = June 2015 | pmid = 25896327 | doi = 10.1158/0008-5472.CAN-14-3650 | doi-access = free | hdl = 10261/123035 | hdl-access = free }}{{cite journal | vauthors = 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 | title = Chitinase 3-like 1 regulates cellular and tissue responses via IL-13 receptor α2 | journal = Cell Reports | volume = 4 | issue = 4 | pages = 830–41 | date = August 2013 | pmid = 23972995 | pmc = 3988532 | doi = 10.1016/j.celrep.2013.07.032 }}

{{Reflist}}

• {{MeshName|Receptors,+Interleukin-13}}

{{Cytokine receptors}}

{{Interleukin receptor modulators}}

{{DEFAULTSORT:Interleukin-13 Receptor}}

Category:Type I cytokine receptors