Cited by 1,545Cytokine Signaling Pathways and InteractionsT-cell and B-cell ImmunologyReceptor Mechanisms and Signaling

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THE IL-4 RECEPTOR: Signaling Mechanisms and Biologic Functions

Nelms, Keats, Keegan, Achsah D., Zamorano, José, Ryan, John J., Paul, William E.·1999·Annual Review of Immunology

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Abstract

Interleukin-4 is a multifunctional cytokine that plays a critical role in the regulation of immune responses. Its effects depend upon binding to and signaling through a receptor complex consisting of the IL-4R alpha chain and the common gamma chain (gamma c), resulting in a series of phosphorylation events mediated by receptor-associated kinases. In turn, these cause the recruitment of mediators of cell growth, of resistance to apoptosis, and of gene activation and differentiation. Here we describe our current understanding of the organization of the IL-4 receptor, of the signaling pathways that are induced as a result of receptor occupancy, and of the various mechanisms through which receptor function is modulated. We particularly emphasize the modular nature of the receptor and the specialization of different receptor regions for distinct functions, most notably the independent regulation of cell growth and gene activation.

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Crossref · 10.1146/annurev.immunol.17.1.701

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Background
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Background
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Background
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Background
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Background
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Background
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Background
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Background
A Gene‐Dosage Effect for Interleukin‐4 Receptor α‐Chain Expression Has an Impact on Th2‐Mediated Allergic Inflammation during Bronchopulmonary Mycosis
Müller, U., Stenzel, W., Köhler, G., Polte, T., Blessing, M., Mann, A., Piehler, D., Brombacher, F., & Alber, G. (2008) · The Journal of Infectious Diseases · doi:10.1086/593068 · Cited by 35
Polymorphisms in the IL4 and IL4RA genes in Colombian patients with rheumatoid arthritis.
Moreno, O. M., González, C. I., Saaibi, D. L., Otero, W., Badillo, R., Martin, J. J., & Ramírez, G. (2007) · PubMed · Cited by 35
IL‐4 receptor alpha chain genetic polymorphism and total IgE levels in the English population: two‐locus haplotypes are more informative than individual SNPs
Bottini, N., Borgiani, P., Otsu, A., Saccucci, P., Stefanini, L., Greco, E., Fontana, L., Hopkin, J. M., Mao, X. ‐., & Shirakawa, T. (2002) · Clinical Genetics · doi:10.1034/j.1399-0004.2002.610408.x · Cited by 35
“The alpha chain of the IL-4 receptor (IL-4RA) constitutes part of receptors for both IL-4 and IL13, which are important cytokines in mediating the isotype switching to IgE, and finally, in the pathogenesis of atopy and allergic diseases (1).”
Background
Tumor Necrosis Factor Receptor–Associated Factor (Traf)2 Represses the T Helper Cell Type 2 Response through Interaction with Nfat-Interacting Protein (Nip45)
Lieberson, R., Mowen, K. A., McBride, K. D., Leautaud, V., Zhang, X., Suh, W., Wu, L., & Glimcher, L. H. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.194.1.89 · Cited by 35
Constrained mixture estimation for analysis and robust classification of clinical time series
Costa, I. G., Schönhuth, A., Hafemeister, C., & Schliep, A. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp222 · Cited by 35
ILC2 Lung-Homing in Cystic Fibrosis Patients: Functional Involvement of CCR6 and Impact on Respiratory Failure
Schulz-Kuhnt, A., Greif, V., Hildner, K. M., Knipfer, L., Döbrönti, M., Zirlik, S., Fuchs, F. S., Atreya, R. N., Zundler, S., López-Posadas, R., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00691 · Cited by 34
“Membranes were incubated overnight at 4◦C with the following primary antibodies: Col VI (Abcam), Col I (Cell Signaling Technology), phospho-STAT3 (Cell Signaling Technology), STAT3 (Cell Signaling Technology), phosphoSTAT6 (Cell Signaling Technology) and STAT6 (Cell Signaling Technology). β-Actin (Cell Signaling Techn…”
BackgroundInfluential
Novel Biological Therapies for Severe Asthma Endotypes
Pelaia, C., Pelaia, G., Crimi, C., Maglio, A., Stanziola, A. A., Calabrese, C., Terracciano, R., Longhini, F., & Vatrella, A. (2022) · Biomedicines · doi:10.3390/biomedicines10051064 · Cited by 35
Conjunctival Goblet Cell Function
García-Posadas, L., Contreras‐Ruiz, L., Soriano-Romaní, L., Dartt, D. A., & Diebold, Y. (2015) · Eye & Contact Lens Science & Clinical Practice · doi:10.1097/icl.0000000000000158 · Cited by 34
“Interleukin 4 is necessary for Th2 lymphocyte differentiation and it is later secreted by these Th2 cells.(71) This pleiotropic cytokine binds to IL-4 receptors to activate signal trans-”
Background
Gene silencing of STAT6 with siRNA ameliorates contact hypersensitivity and allergic rhinitis
Hosoya, K., Satoh, T., Yamamoto, Y., Saeki, K., Igawa, K., Okano, M., Moriya, T., Imamura, O., Nemoto, Y., & Yokozeki, H. (2010) · Allergy · doi:10.1111/j.1398-9995.2010.02440.x · Cited by 34
“Binding of IL-4 or IL-13 induces phosphorylation of STAT6 via JAK1 and JAK3 kinases, resulting in the homodimer formation and translocation to the nucleus (1).”
Background
Neuroprotective effect of sodium ferulate and signal transduction mechanisms in the aged rat hippocampus
Jin, Y., Yan, E., Li, X., Fan, Y., Zhao, Y., Liu, Z., & Liu, W. (2008) · Acta Pharmacologica Sinica · doi:10.1111/j.1745-7254.2008.00848.x · Cited by 34
B cell proliferation following CD40 stimulation results in the expression and activation of Src protein tyrosine kinase
Néron, S., Suck, G., Ma, X., Sakac, D., Roy, A., Katsman, Y., Dussault, N., Racine, C., & Branch, D. R. (2006) · International Immunology · doi:10.1093/intimm/dxh377 · Cited by 34
Kinetics of GATA‐3 gene expression in early polarizing and committed human T cells
Lantelme, E., Mantovani, S., Palermo, B., Campanelli, R., Sallusto, F., & Giachino, C. (2001) · Immunology · doi:10.1046/j.1365-2567.2001.01168.x · Cited by 34
Lethal Hepatitis After Gene Transfer of IL-4 in the Liver Is Independent of Immune Responses and Dependent on Apoptosis of Hepatocytes: A Rodent Model of IL-4-Induced Hepatitis
Guillot, C., Coathalem, H., Chetritt, J. J., David, A., Lowenstein, P. R., Gilbert, E., Tesson, L., van Rooijen, N., Cuturi, M. C., Soulillou, J., et al. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.8.5225 · Cited by 34
“The IL-4R a intracellular segment contains distinct domains responsible for cell proliferation, regulation of apoptosis, and gene expression (39).”
Background
Mucin biosynthesis: upregulation of core 2 β1,6N-acetylglucosaminyltransferase by retinoic acid and Th2 cytokines in a human airway epithelial cell line
Beum, P. V., Basma, H., Bastola, D. R., & Cheng, P. (2004) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00370.2003 · Cited by 34
Polymorphisms in the interleukin 4, interleukin 4 receptor and interleukin 13 genes and allergic phenotype: A case control study
Narożna, B., Hoffmann, A., Sobkowiak, P., Schöneich, N., Bręborowicz, A., & Szczepankiewicz, A. (2015) · Advances in Medical Sciences · doi:10.1016/j.advms.2015.07.003 · Cited by 33
IL-4 Engagement of the Type I IL-4 Receptor Complex Enhances Mouse Eosinophil Migration to Eotaxin-1 In Vitro
Heller, N. M., Gwinn, W. M., Donnelly, R. P., Constant, S. L., & Keegan, A. D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039673 · Cited by 33
“These results are consistent with equilibrium binding studies on primary cells showing that the numbers of IL-4 and IL-13 binding sites range from 50–5000 per cell [24].”
Result
Impact of cytokine and cytokine receptor gene polymorphisms on cellular immunity after smallpox vaccination
Ovsyannikova, I. G., Haralambieva, I. H., Kennedy, R. B., Pankratz, V. S., Vierkant, R. A., Jacobson, R. M., & Poland, G. A. (2012) · Gene · doi:10.1016/j.gene.2012.08.021 · Cited by 33
“…between the IL4 gene haplotype, which includes the known functional SNP rs2243250, and a decreased risk for fever might be the influence of a Th2 type-modulated increase in IL-4 production and concomitant suppression of IFN-γ production and Th1 responses (Nelms et al., 1999; Stanley et al., 2007).”
Cell-Autonomous CCL5 Transcription by Memory CD8 T Cells Is Regulated by IL-4
Marçais, A., Coupet, C., Walzer, T., Tomkowiak, M., Ghittoni, R., & Marvel, J. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.7.4451 · Cited by 33
“STAT6 is the main transcription factor activated by IL-4 (23, 31, 32), Indeed, when IL-4 binds to its receptor it induces the activation of JAK 1 and 3 that, in turn, phosphorylate cytoplasmic STAT6, which then undergoes dimerization and is translocated to the nucleus where it can either activate (23) or repress gene…”
Background
Interleukin-4 (IL-4) may regulate alternative activation of macrophage-like cells in chickens: A sequential study using novel and specific neutralizing monoclonal antibodies against chicken IL-4
Chaudhari, A. A., Kim, W. H., & Lillehoj, H. S. (2018) · Veterinary Immunology and Immunopathology · doi:10.1016/j.vetimm.2018.10.011 · Cited by 33
Cytokine profiles in cerebrospinal fluid of patients with meningitis at a tertiary general hospital in China
Liu, Q., Gao, Y., Zhang, B., Sun, F., Yang, Q., Liu, Y., Wu, J., Chen, K., Weng, X., Zhang, W., et al. (2018) · Journal of Microbiology Immunology and Infection · doi:10.1016/j.jmii.2018.08.019 · Cited by 34
Increases in ambient air pollutants during pregnancy are linked to increases in methylation of IL4, IL10, and IFNγ
Aguilera, J., Han, X., Cao, S., Balmes, J. R., Lurmann, F. W., Tyner, T. R., Lutzker, L., Noth, E. M., Hammond, S. K., Sampath, V., et al. (2022) · Clinical Epigenetics · doi:10.1186/s13148-022-01254-2 · Cited by 34
“IL4 aids in the polarization of antigen-stimulated naïve Th cells into Th2 effector cells and propagates Th2 responses, while IL10 downregulates Th1 cells [19, 29].”
Background
Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma
Nilsson, M., Rhedin, M., Hendrickx, R., Berglund, S., Piras, A., Blomgran, P., Cavallin, A., Collins, M., Dahl, G., Dekkak, B., et al. (2022) · Drug Design Development and Therapy · doi:10.2147/dddt.s354291 · Cited by 33
“In the context of asthma, IL-4 can signal through two alternative receptor complexes: an IL-4 receptor α (IL-4Rα)/IL-2 common γ-chain receptor complex, which recruits JAK1 and JAK3, or an IL-4Rα/IL-13Rα receptor complex, which recruits JAK1 and JAK2 or TYK2.(19,21) IL-13 is also able to signal through the IL-4Rα/IL-13…”
Background
Differential Regulation of IL-4Rα Expression by Antigen versus Cytokine Stimulation Characterizes Th2 Progression In Vivo
Perona‐Wright, G., Mohrs, K., Mayer, K. D., & Mohrs, M. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0902408 · Cited by 31
“IL-4 signals through either the type I IL-4 receptor, which com- prises IL-4Ra and the common g (gc) chain, or the type II IL-4 receptor in which IL-4Ra is paired with IL-13Ra1 (12).”
BackgroundInfluential
Quercetin inhibits transcriptional up-regulation of histamine H1 receptor via suppressing protein kinase C-δ/extracellular signal-regulated kinase/poly(ADP-ribose) polymerase-1 signaling pathway in HeLa cells
Hattori, M., Mizuguchi, H., Baba, Y., Ono, S., Nakano, T., Zhang, Q., Sasaki, Y., Kobayashi, M., Kitamura, Y., Takeda, N., et al. (2013) · International Immunopharmacology · doi:10.1016/j.intimp.2012.12.030 · Cited by 33
Cytokine gene transfer for cancer therapy
Podhajcer, O. L., Lopez, M. V., & Mazzolini, G. D. (2007) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2007.01.014 · Cited by 32
“Among other interesting cytokines evaluated in preclinical trials, IL-4 is a paradigmatic Th2 cytokine as mice lacking either IL-4 or IL-4 receptors fail to develop Th2 cells [25].”
Background
γδ T Cells and B Cells
Born, W. K., Huang, Y., Reinhardt, R. L., Huang, H., Sun, D., & O’Brien, R. L. (2017) · Advances in immunology · doi:10.1016/bs.ai.2017.01.002 · Cited by 35
Allergy and autoinflammation drive persistent systemic inflammatory response in Meniere Disease: A longitudinal study
Frejo, L., Cara, F. E., Flook, M., Robles-Bolívar, P., Escalera‐Balsera, A., Montilla-Ibáñez, M. A., Domínguez‐Durán, E., Martinez-Martinez, M., Perez‐Carpena, P., & Lopez-Escamez, J. A. (2024) · Clinical Immunology · doi:10.1016/j.clim.2024.110413 · Cited by 38
Interleukin‐4 single nucleotide polymorphisms in juvenile systemic lupus erythematosus
Mahmoudi, M., Tahghighi, F., Ziaee, V., Harsini, S., Rezaei, A., Soltani, S., Sadr, M., Moradinejad, M.-H., Aghighi, Y., & Rezaei, N. (2014) · International Journal of Immunogenetics · doi:10.1111/iji.12152 · Cited by 32
“IL-4 has been identified as an important actor in regulating the differentiation of antigen-stimulated naive T cells to develop into T helper 2 (Th2), which is capable of secreting cytokines such as IL-4, IL-5, IL-6 and IL-10, and contributes towards humoral immune responses (Mosmann & Coffman, 1989; Nelms et al., 199…”
Background
Disruption of the γc cytokine network in T cells during HIV infection
Sirskyj, D., Thèze, J., Kumar, A., & Kryworuchko, M. (2008) · Cytokine · doi:10.1016/j.cyto.2008.03.001 · Cited by 32
RETRACTED: Interleukin‐4 activates androgen receptor through CBP/p300
Lee, S. O., Chun, J. Y., Nadiminty, N., Lou, W., Feng, S., & Gao, A. C. (2008) · The Prostate · doi:10.1002/pros.20865 · Cited by 33
“In addition to its effect on immune cells, IL-4 has a variety of other functions including effects on hematopoietic tissues, tissue adhesion and inflammation (2).”
Background
Retracted
Transfer of in vivo primed transgenic T cells supports allergic lung inflammation and FIZZ1 and Ym1 production in an IL-4Rα and STAT6 dependent manner
Dasgupta, P., Chapoval, S. P., Smith, E., & Keegan, A. D. (2011) · BMC Immunology · doi:10.1186/1471-2172-12-60 · Cited by 32
“Apart from TH2 cells, IL-4 and IL-13 are also secreted by natural killer (NK) T cells, basophils, mast cells, macrophages and activated eosinophils (reviewed in [12]).”
Background
Contribution of Interleukin‐4–Induced Epithelial Cell Senescence to Glandular Fibrosis in IgG4‐Related Sialadenitis
Min, S., Zhu, M., Mao, X., Li, W., Wei, T., Mei, M., Zhang, Y., Wu, L., Yu, G., & Cong, X. (2021) · Arthritis & Rheumatology · doi:10.1002/art.42052 · Cited by 33
“The Th2-derived cytokine IL-4 is pleiotropic and may be involved in differentiation, proliferation, or apoptosis depending on the cell type (39,40).”
Background
Dual Modulation of Airway Smooth Muscle Contraction by Th2 Cytokines via Matrix Metalloproteinase-1 Production
Ohta, Y., Hayashi, M., Kanemaru, T., Abe, K., Ito, Y., & Oike, M. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.6.4191 · Cited by 32
“It is known that the IL-4R chain binds IL-4 and dimerizes with IL-13R 1 to form a type II IL-4R in nonhematopoietic cells (27).”
Background
Interleukin 4, interleukin 4 receptor‐α and interleukin 10 gene polymorphisms in Chagas disease
Flórez-Vargas, O., Martin, J. J., & González, C. I. (2011) · Parasite Immunology · doi:10.1111/j.1365-3024.2011.01314.x · Cited by 32
Natural Tregs and autoimmunity
Cava, A. L. (2009) · Frontiers in bioscience · doi:10.2741/3247 · Cited by 31
Toxin-Based Targeted Therapy for Malignant Brain Tumors
Chandramohan, V., Sampson, J. H., Pastan, I. H., & Bigner, D. D. (2012) · Clinical and Developmental Immunology · doi:10.1155/2012/480429 · Cited by 32
“IL-4 regulates the differentiation of antigen-stimulated naive T cells and the specificity of immunoglobulin class switching by B cells [62].”
BackgroundInfluential
Akt cross-links IL-4 priming, stem cell factor signaling, and IgE-dependent activation in mature human mast cells
Feuser, K., Feilhauer, K., Staib, L., Bischoff, S. C., & Lorentz, A. (2010) · Molecular Immunology · doi:10.1016/j.molimm.2010.10.010 · Cited by 32
A New Mechanism for Inhalational Priming: IL-4 Bypasses Innate Immune Signals
Dittrich, A., Chen, H., Xu, L., Ranney, P., Connolly, S., Yarovinsky, T. O., & Bottomly, H. K. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.10.7307 · Cited by 32
“IL-4 has been known for decades to be a cytokine with a pivotal role in the development of Th2-polarized T cells (11, 12), and hence Th2-polarized immune responses (13–17), resulting from its pleiotropic effects, which encompass hematopoietic and nonhematopoietic cells (18).”
Background
Interleukin-4 in patients with prostate cancer.
Ueda, T., Sadar, M. D., Suzuki, H., Akakura, K., Sakamoto, S., Shimbo, M., Suyama, T., Imamoto, T., Komiya, A., Naya, Y., et al. (2005) · PubMed · Cited by 32
Interleukin-4: A multifunctional cytokine
Zamorano, J. L., Perez-G, M., & la Investigación, U. D. R. D. I. C. P. (2003) · Cited by 32
R egulation of RAW264.7 macrophage polarization on smooth and rough surface topographies by galectin‐3
Kianoush, F., Nematollahi, M., Waterfield, J. D., & Brunette, D. M. (2017) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.36107 · Cited by 32
IL-4 Inhibits the Expression of Mouse Formyl Peptide Receptor 2, a Receptor for Amyloid β1–42, in TNF-α-Activated Microglia
Iribarren, P., Chen, K., Hu, J., Zhang, X., Gong, W., & Wang, J. M. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.9.6100 · Cited by 32
“Furthermore, our study revealed that up-regulation of the phosphatase PP2A, in a manner independent of Stat6, may play an essential role in IL4-mediated attenuation of the TNF- signaling cascade in microglial cells and the resultant expression mFPR2, the mouse homolog of human FPRL1, a functional receptor for the AD-a…”
BackgroundInfluential
IL-4 Induces the Proteolytic Processing of Mast Cell STAT6
Sherman, M. A., Powell, D. R., & Brown, M. A. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.7.3811 · Cited by 34

Authors: Nelms, K., Keegan, A. D., Zamorano, J., Ryan, J. J., & Paul, W. E.
Affiliations: National Institutes of Health (US)
Corresponding author: Nelms, Keats
Paul, William E.
ORCID: Keegan, Achsah D.
Ryan, John J.
Venue: Annual Review of Immunology
Publisher: Annual Reviews
Published: 1999-04
Volume: 17
Issue: 1
Pages: 701-738
ISSN: 0732-0582 (ISSN-L)
1545-3278
DOI: 10.1146/annurev.immunol.17.1.701
OpenAlex: W2144120552
Cited by: 1,545
References: 190
Citations by year: 2026: 17 · 2025: 27 · 2024: 52 · 2023: 36 · 2022: 54 · 2021: 43 · 2020: 50 · 2019: 44 · 2018: 54 · 2017: 49 · 2016: 52 · 2015: 56 · 2014: 72 · 2013: 52 · 2012: 55
FWCI: 6.85
Type: journal article
Language: en
Open access: closed
Locations: Annual Review of Immunology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords: IL-4, IL-4 receptor, common gamma chain, receptor signaling, receptor phosphorylation, cell growth regulation, apoptosis resistance, gene activation, T cell differentiation, cytokine signaling
MeSH terms: Amino Acid Sequence, Animals, Humans, Molecular Sequence Data, Phosphoproteins, Signal Transduction, Trans-Activators, Interleukin-4, Protein Tyrosine Phosphatases, Calcium-Calmodulin-Dependent Protein Kinases, Mice, Knockout, Receptors, Interleukin-4, Mitogen-Activated Protein Kinases, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, STAT6 Transcription Factor, Mice, Insulin Receptor Substrate Proteins

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THE IL-4 RECEPTOR: Signaling Mechanisms and Biologic Functions

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