Skip to main content
SpringerLink
Log in

Two copies of the genes encoding the subunits of putative interleukin (IL)-4/IL-13 receptors, IL-4Rα, IL-13Rα1 and IL-13Rα2, have been identified in rainbow trout (Oncorhynchus mykiss) and have complex patterns of expression and modulation

  • Original Paper
  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

Mammalian interleukin-4 (IL-4) and IL-13 are T helper type 2 (Th2) cytokines with pleiotropic functions in immunity. They signal through receptors containing IL-4Rα and IL-2Rγ or IL-13Rα1. In addition, a decoy receptor, IL-13Rα2, is known to exist and modulates the function of IL-13. The existence of fish orthologues to mammalian IL-4 and IL-13 is still under debate. However, the receptor chains have been predicted in zebrafish, and we have previously cloned IL-2Rγ and IL-13Rα2 in rainbow trout. In this study, we have cloned a further five novel trout IL-4/13 receptors. Thus, each of the IL-4Rα, IL-13Rα1 and IL-13Rα2 chains has two copies. The identities of the receptors is supported by homology analysis, characteristic domain structure, phylogenetic tree analysis and synteny analysis in zebrafish. However, the characteristic WSXWS motif of structural importance in mammalian type I cytokine receptors is missing in all fish IL-4Rα and IL-13Rα1 molecules. All the receptors have a characteristic domain structure that is similar to their mammalian counterparts except for IL-13Rα1b that has the N-terminal Ig domain missing. Since this Ig domain is a specific and critical binding unit for IL-13 but not for IL-4 signalling, its absence potentially converts the IL-13Rα1b into a receptor that can only signal via IL-4 ligation. The existence of duplicated receptor genes perhaps suggests that more ligands still remain to be discovered that will bind these receptors. The duplicated receptors are differentially expressed in most tissues and cell lines examined, and their expression can be modulated by LPS, polyIC and IFN-γ in cell lines. In contrast, the T-cell stimulant phytohaemagglutinin increased the expression of IL-4Rα1 and IL-4Rα2, but not IL-13Rα1/2, suggesting a role of an IL-4-like molecule in T-cell growth/activation in fish.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Akashi M, Shaw G, Hachiya M, Elstner E, Suzuki G, Koeffler P (1994) Number and location of AUUUA motifs: role in regulating transiently expressed RNAs. Blood 83:3182–3187

    PubMed  CAS  Google Scholar 

  • Andrews AL, Holloway JW, Holgate ST, Davies DE (2006) IL-4 receptor alpha is an important modulator of IL-4 and IL-13 receptor binding: implications for the development of therapeutic targets. J Immunol 176:7456–7461

    PubMed  CAS  Google Scholar 

  • Arima K, Sato K, Tanaka G, Kanaji S, Terada T, Honjo E, Kuroki R, Matsuo Y, Izuhara K (2005) Characterization of the interaction between interleukin-13 and interleukin-13 receptors. J Biol Chem 280:24915–24922

    Article  PubMed  CAS  Google Scholar 

  • Avery S, Rothwell L, Degen WDJ, Schijns VEJC, Young J, Kaufman J, Kaiser P (2004) Characterization of the first nonmammalian T2 cytokine gene cluster: the cluster contains functional single-copy genes for IL-3, IL-4, IL-13, and GM-CSF, a gene for IL-5 that appears to be a pseudogene, and a gene encoding another cytokinelike transcript, KK34. J Interferon Cytokine Res 24:600–610

    PubMed  CAS  Google Scholar 

  • Baumgartner JW, Wells CA, Chen CM, Waters MJ (1994) The role of the WSXWS equivalent motif in growth hormone receptor function. J Biol Chem 269:29094–29101

    PubMed  CAS  Google Scholar 

  • Bazan JF (1990) Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci USA 87:6934–6938

    Article  PubMed  CAS  Google Scholar 

  • Bird S, and Secombes CJ (2006) Danio rerio partial mRNA for interleukin-4. GenBank accession no. AM403245

  • Boulay JL, O'Shea JJ, Paul WE (2003) Molecular phylogeny within type I cytokines and their cognate receptors. Immunity 19:159–163

    Article  PubMed  CAS  Google Scholar 

  • Campanella JJ, Bitincka L, Smalley J (2003) MatGAT: an application that generates similarity/identity matrices using protein or DNA sequences. BMC Bioinform 4:29

    Article  Google Scholar 

  • Chenna R, Sugawara H, Koike T, Lopez R, Gibson TJ, Higgins DG, Thompson JD (2003) Multiple sequence alignment with the Clustal series of programs. Nucleic Acids Res 31:3497–3500

    Article  PubMed  CAS  Google Scholar 

  • David M, Ford D, Bertoglio J, Maizel AL, Pierre J (2001) Induction of the IL-13 receptor alpha2-chain by IL-4 and IL-13 in human keratinocytes: involvement of STAT6, ERK and p38 MAPK pathways. Oncogene 20:6660–6668

    Article  PubMed  CAS  Google Scholar 

  • Emanuelsson O, Brunak S, von Heijne G, Nielsen H (2007) Locating proteins in the cell using TargetP, SignalP and related tools. Nat Protoc 2:953–971

    Article  PubMed  CAS  Google Scholar 

  • Ganassin RC, Bols NC (1998) Development of a monocyte/macrophage-like cell line, RTS11, from rainbow trout spleen. Fish Shellfish Immunol 8:457–476

    Article  Google Scholar 

  • Gasteiger E, Hoogland C, Gattiker A, Duvaud S, Wilkins MR, Appel RD, Bairoch A (2005) Protein identification and analysis tools on the ExPASy Server. In: JM Walker (ed) The proteomics protocols handbook. Humana, Totowa, pp 571–607.

  • Hage T, Sebald W, Reinemer P (1999) Crystal structure of the interleukin-4/receptor alpha chain complex reveals a mosaic binding interface. Cell 97:271–281

    Article  PubMed  CAS  Google Scholar 

  • Hershey GK (2003) IL-13 receptors and signaling pathways: an evolving web. J Allergy Clin Immunol 111:677–690; quiz 691

    Google Scholar 

  • Hilton DJ, Watowich SS, Katz L, Lodish HF (1996) Saturation mutagenesis of the WSXWS motif of the erythropoietin receptor. J Biol Chem 271:4699–4708

    Article  PubMed  CAS  Google Scholar 

  • Hofmann K, Stoffel W (1993) TMbase—a database of membrane spanning proteins segments. Biol Chem Hoppe Seyler 373:166

    Google Scholar 

  • Holland JW, Karim A, Wang T, Alnabulsi A, Scott J, Collet B, Mughal MS, Secombes CJ, Bird S (2010) Molecular cloning and characterization of interferon regulatory factors 4 and 8 (IRF-4 and IRF-8) in rainbow trout, Oncorhynchus mykiss. Fish Shellfish Immunol 29:157–166

    Google Scholar 

  • Ito T, Suzuki S, Kanaji S, Shiraishi H, Ohta S, Arima K, Tanaka G, Tamada T, Honjo E, Garcia KC, Kuroki R, Izuhara K (2009) Distinct structural requirements for interleukin-4 (IL-4) and IL-13 binding to the shared IL-13 receptor facilitate cellular tuning of cytokine responsiveness. J Biol Chem 284:24289–24296

    Article  PubMed  CAS  Google Scholar 

  • Junttila IS, Mizukami K, Dickensheets H, Meier-Schellersheim M, Yamane H, Donnelly RP, Paul WE (2008) Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac regulates relative cytokine sensitivity. J Exp Med 205:2595–2608

    Article  PubMed  CAS  Google Scholar 

  • Kioi M, Seetharam S, Puri RK (2006) N-linked glycosylation of IL-13R alpha2 is essential for optimal IL-13 inhibitory activity. FASEB J 20:2378–2380

    Article  PubMed  CAS  Google Scholar 

  • Koop BF, von Schalburg KR, Leong J, Walker N, Lieph R, Cooper GA, Robb A, Beetz-Sargent M, Holt RA, Moore R, Brahmbhatt S, Rosner J, Rexroad CE 3rd, McGowan CR, Davidson WS (2008) A salmonid EST genomic study: genes, duplications, phylogeny and microarrays. BMC Genomics 9:545

    Article  PubMed  Google Scholar 

  • LaPorte SL, Juo ZS, Vaclavikova J, Colf LA, Qi X, Heller NM, Keegan AD, Garcia KC (2008) Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system. Cell 132:259–272

    Article  PubMed  CAS  Google Scholar 

  • Lee LE, Clemons JH, Bechtel DG, Caldwell SJ, Han KB, Pasitschniak-Arts M, Mosser DD, Bols NC (1993) Development and characterization of a rainbow trout liver cell line expressing cytochrome P450-dependent monooxygenase activity. Cell Biol Toxicol 9:279–294

    Article  PubMed  CAS  Google Scholar 

  • Li JH, Shao JZ, Xiang LX, Wen Y (2007) Cloning, characterization and expression analysis of pufferfish interleukin-4 cDNA: the first evidence of Th2-type cytokine in fish. Mol Immunol 44:2078–2086

    Article  PubMed  CAS  Google Scholar 

  • Liongue C, Ward AC (2007) Evolution of class I cytokine receptors. BMC Evol Biol 7:120

    Article  PubMed  Google Scholar 

  • Lockyer AE, Jones CS, Noble LR, Verspoor E, Holland J, Secombes CJ (2001) Isolation and characterisation of a putative interleukin 13 receptor a2 sequence from rainbow trout (Oncorhynchus mykiss). Fish Shellfish Immunol 11:541–546

    Article  PubMed  CAS  Google Scholar 

  • Lupardus PJ, Birnbaum ME, Garcia KC (2010) Molecular basis for shared cytokine recognition revealed in the structure of an unusually high affinity complex between IL-13 and IL-13Ralpha2. Structure 18:332–342

    Google Scholar 

  • Marsden RL, McGuffin LJ, Jones DT (2002) Rapid protein domain assignment from amino acid sequence using predicted secondary structure. Protein Sci 11:2814–2824

    Article  PubMed  CAS  Google Scholar 

  • Murakami M, Narazaki M, Hibi M, Yawata H, Yasukawa K, Hamaguchi M, Taga T, Kishimoto T (1991) Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family. Proc Natl Acad Sci USA 88:11349–11353

    Article  PubMed  CAS  Google Scholar 

  • Murray PJ (2007) The JAK–STAT signaling pathway: input and output integration. J Immunol 178:2623–2629

    PubMed  CAS  Google Scholar 

  • Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE (1999) The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol 17:701–738

    Article  PubMed  CAS  Google Scholar 

  • Ohtani M, Hayashi N, Hashimoto K, Nakanishi T, Dijkstra JM (2008) Comprehensive clarification of two paralogous interleukin 4/13 loci in teleost fish. Immunogenetics 60:383–397

    Article  PubMed  CAS  Google Scholar 

  • Orchansky PL, Kwan R, Lee F, Schrader JW (1999) Characterization of the cytoplasmic domain of interleukin-13 receptor-alpha. J Biol Chem 274:20818–20825

    Article  PubMed  CAS  Google Scholar 

  • Osborne J (2002) Notes on the use of data transformations. Practical Assessment, Research & Evaluation, 8, 6

  • Rahaman SO, Sharma P, Harbor PC, Aman MJ, Vogelbaum MA, Haque SJ (2002) IL-13R(alpha)2, a decoy receptor for IL-13 acts as an inhibitor of IL-4-dependent signal transduction in glioblastoma cells. Cancer Res 62:1103–1109

    PubMed  CAS  Google Scholar 

  • Ramalingam TR, Pesce JT, Sheikh F, Cheever AW, Mentink-Kane MM, Wilson MS, Stevens S, Valenzuela DM, Murphy AJ, Yancopoulos GD, Urban JF Jr, Donnelly RP, Wynn TA (2008) Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor alpha1 chain. Nat Immunol 9:25–33

    Article  PubMed  CAS  Google Scholar 

  • Reimer T, Brcic M, Schweizer M, Jungi TW (2008) poly(I:C) and LPS induce distinct IRF3 and NF-kappaB signaling during type-I IFN and TNF responses in human macrophages. J Leukoc Biol 83:1249–1257

    Article  PubMed  CAS  Google Scholar 

  • Rogan DF, Cousins DJ, Santangelo S, Ioannou PA, Antoniou M, Lee TH, Staynov DZ (2004) Analysis of intergenic transcription in the human IL-4/IL-13 gene cluster. Proc Natl Acad Sci USA 101:2446–2451

    Article  PubMed  CAS  Google Scholar 

  • Schirmer K, Chan AG, Greenberg BM, Dixon DG, Bols NC (1998) Ability of 16 priority PAHs to be photocytotoxic to a cell line from the rainbow trout gill. Toxicology 127:143–155

    Article  PubMed  CAS  Google Scholar 

  • Schulte T, Kurrle R, Rollinghoff M, Gessner A (1997) Molecular characterization and functional analysis of murine interleukin 4 receptor allotypes. J Exp Med 186:1419–1429

    Article  PubMed  CAS  Google Scholar 

  • Tamura K, Dudley J, Nei M, Kumar S (2007) MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol 24:1596–1599

    Article  PubMed  CAS  Google Scholar 

  • Usacheva A, Sandoval R, Domanski P, Kotenko SV, Nelms K, Goldsmith MA, Colamonici OR (2002) Contribution of the Box 1 and Box 2 motifs of cytokine receptors to Jak1 association and activation. J Biol Chem 277:48220–48226

    Article  PubMed  CAS  Google Scholar 

  • Wakahara S, Konoshita T, Mizuno S, Motomura M, Aoyama C, Makino Y, Kato N, Koni I, Miyamori I (2007) Synergistic expression of angiotensin-converting enzyme (ACE) and ACE2 in human renal tissue and confounding effects of hypertension on the ACE to ACE2 ratio. Endocrinology 148:2453–2457

    Article  PubMed  CAS  Google Scholar 

  • Wang T, Diaz-Rosales P, Costa MM, Campbell S, Snow M, Collet B, Martin SAM, Secombes CJ (2011) The first functional characterisation of a non-mammalian interleukin (IL)-21: rainbow trout Oncorhynchus mykiss IL-21 up-regulates the expression of the T helper cell signature cytokines interferon-γ, IL-10 and IL-22. J Immunol 186:. doi:10.4049/jimmunol.1001203

  • Wang T, Secombes CJ (2001) Cloning and expression of a putative common cytokine receptor gamma chain (gammaC) gene in rainbow trout (Oncorhynchus mykiss). Fish Shellfish Immunol 11:233–244

    Article  PubMed  CAS  Google Scholar 

  • Wang T, Secombes CJ (2003) Complete sequencing and expression of three complement components, C1r, C4 and C1 inhibitor, of the classical activation pathway of the complement system in rainbow trout Oncorhynchus mykiss. Immunogenetics 55:615–628

    Article  PubMed  CAS  Google Scholar 

  • Wang T, Holland JW, Bols N, Secombes CJ (2005) Cloning and expression of the first nonmammalian interleukin-11 gene in rainbow trout Oncorhynchus mykiss. FEBS J 272:1136–1147

    Article  PubMed  CAS  Google Scholar 

  • Wang T, Hanington PC, Belosevic M, Secombes CJ (2008) Two macrophage colony-stimulating factor genes exist in fish that differ in gene organization and are differentially expressed. J Immunol 181:3310–3322

    PubMed  CAS  Google Scholar 

  • Wang T, Bird S, Koussounadis A, Holland JW, Carrington A, Zou J, Secombes CJ (2009) Identification of a novel IL-1 cytokine family member in teleost fish. J Immunol 183:962–974

    Article  PubMed  CAS  Google Scholar 

  • Weidemann T, Hofinger S, Muller K, Auer M (2007) Beyond dimerization: a membrane-dependent activation model for interleukin-4 receptor-mediated signalling. J Mol Biol 366:1365–1373

    Article  PubMed  CAS  Google Scholar 

  • Wills-Karp M, and Finkelman FD (2008) Untangling the complex web of IL-4- and IL-13-mediated signaling pathways. Sci Signal 1:pe55

    Google Scholar 

  • Wolf K, Quimby MC (1962) Established eurythermic lines of fish cells in vitro. Science 135:1065

    Article  PubMed  CAS  Google Scholar 

  • Yan A, Lennarz WJ (2005) Unraveling the mechanism of protein N-glycosylation. J Biol Chem 280:3121–3124

    Article  PubMed  CAS  Google Scholar 

  • Yuan JS, Reed A, Chen F, Stewart CN Jr (2006) Statistical analysis of real-time PCR data. BMC Bioinform 7:85

    Article  Google Scholar 

  • Zhu J, Paul WE (2010) Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev 238:247–262

    Article  PubMed  CAS  Google Scholar 

  • Zou J, Wang T, Hirono I, Aoki T, Inagawa H, Honda T, Soma GI, Ototake M, Nakanishi T, Ellis AE, Secombes CJ (2002) Differential expression of two tumor necrosis factor genes in rainbow trout Oncorhynchus mykiss. Dev Comp Immunol 26:161–172

    Article  PubMed  CAS  Google Scholar 

  • Zou J, Carrington A, Collet B, Dijkstra JM, Yoshiura Y, Bols N, Secombes C (2005) Identification and bioactivities of IFN-gamma in rainbow trout Oncorhynchus mykiss: the first Th1-type cytokine characterized functionally in fish. J Immunol 175:2484–2494

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported financially by Contract No. 513692 (Aquafirst) and 007103 (IMAQUANIM—Improved Immunity of Aquacultured Animals) from the European Commission. Dr Costa was supported by an Ángeles Alvariño postdoctoral contract from the Consejo Superior de Investigaciones Científicas (CSIC) and the Xunta de Galicia.

Author information

Authors and Affiliations

  1. Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 2TZ, UK

    Tiehui Wang, Wenshu Huang, Maria M. Costa, Samuel A. M. Martin & Christopher J. Secombes

  2. Fisheries College, Jimei University, Xiamen, Fujian, 361021, People’s Republic of China

    Wenshu Huang

  3. Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Científicas (CSIC), Eduardo Cabello 6, Vigo, Spain

    Maria M. Costa

Authors
  1. Tiehui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wenshu Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria M. Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Samuel A. M. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christopher J. Secombes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christopher J. Secombes.

Additional information

The nucleotide sequence data will appear in the EMBL/DDBJ/GenBank nucleotide sequence database under the following accession numbers: AJ634731 (IL-4Rα1), FN824519 (IL-4Rα2), FN824520 (IL-13Rα1a), FN824521(IL-13Rα1b) and FN824522 (IL-13Rα2b).

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 117 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, T., Huang, W., Costa, M.M. et al. Two copies of the genes encoding the subunits of putative interleukin (IL)-4/IL-13 receptors, IL-4Rα, IL-13Rα1 and IL-13Rα2, have been identified in rainbow trout (Oncorhynchus mykiss) and have complex patterns of expression and modulation. Immunogenetics 63, 235–253 (2011). https://doi.org/10.1007/s00251-010-0508-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-010-0508-2

Keywords

Search

Navigation