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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Method
Interleukin-8 favors pro-inflammatory activity of human monocytes/macrophages
Meniailo, M. E., Malashchenko, V. V., Шмаров, В. А., Газатова, Н. Д., Melashchenko, O. B., Goncharov, A. G., Seledtsova, G. V., & Seledtsov, V. I. (2018) · International Immunopharmacology · doi:10.1016/j.intimp.2018.01.036 · Cited by 99
IL-4 Receptor Signaling in Clara Cells Is Required for Allergen-Induced Mucus Production
Kuperman, D. A., Huang, X., Nguyenvu, L. T., Hölscher, C., Brombacher, F., & Erle, D. J. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.6.3746 · Cited by 99
“IL-4R signaling in both T cells and B cells is critical for IgE production (18).”
Background
Cytokines and inflammation in adipogenesis: an updated review
Jiang, N., Yao, L., Shu, T., & Wang, J. (2018) · Frontiers of Medicine · doi:10.1007/s11684-018-0625-0 · Cited by 104
NFIL3/E4BP4 controls type 2 T helper cell cytokine expression
Kashiwada, M., Cassel, S. L., Colgan, J. D., & Rothman, P. B. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.111 · Cited by 98
“Furthermore, IL-4 upregulates MHC class II on B cells and IgE receptors on inflammatory cells, resulting in the enhancement of antigen presenting ability to T cells and IgE-mediated secretion of inflammatory mediators, respec- tively (Nelms et al, 1999).”
Background
Interleukin-4 receptor signaling and its binding mechanism: A therapeutic insight from inhibitors tool box
Ul‐Haq, Z., Naz, S., & Mesaik, M. A. (2016) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2016.04.002 · Cited by 98
“cells, and eosinophils, beside Th2 lymphocytes [1].”
BackgroundInfluential
Anti-Inflammatory Activity of Inhaled IL-4 Receptor-α Antisense Oligonucleotide in Mice
Karras, J. G., Crosby, J. R., Guha, M., Tung, D., Miller, D. A., Gaarde, W. A., Geary, R. S., Monia, B. P., & Gregory, S. A. (2006) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2005-0456oc · Cited by 95
“As a common signaling chain of both the IL-4 and IL-13 receptors, IL-4R functions as a key intermediary protein in Th2 cytokine responses ( 7 ).”
Background
Cytokines and Cytokine Receptors
O’Shea, J. J., Gadina, M., & Siegel, R. M. (2019) · Elsevier eBooks · doi:10.1016/b978-0-7020-6896-6.00009-0 · Cited by 104
Optimization of selenylation modification for garlic polysaccharide based on immune-enhancing activity
Gao, Z., Chen, J., Qiu, S., Li, Y., Wang, D., Liu, C., Li, X., Hou, R., Yue, C., Liu, J., et al. (2015) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2015.09.065 · Cited by 96
Integration of cytokine and heterologous receptor signaling pathways
Bezbradica, J. S., & Medzhitov, R. M. (2009) · Nature Immunology · doi:10.1038/ni.1713 · Cited by 97
“In T cells, for example, phosphorylated IL-4R recruits STAT6, but also PTB-containing IRS-1, IRS-2, Shc and perhaps other, yet to be identified protein”
Background
Phage display selection of peptides that home to atherosclerotic plaques: IL‐4 receptor as a candidate target in atherosclerosis
Hong, H.-Y., Lee, H. Y., Kwak, W., Yoo, J., Na, M., So, I. S., Kwon, T., Park, H., Huh, S., Oh, G. T., et al. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00189.x · Cited by 96
“Type I receptor is present in haematopoietic cells, while type II receptor is in haematopoietic cells of the myeloid lineage, such as macrophages and eosinophils, and in many other cell types, such as endothelial cells and fibroblasts [17, 18].”
Background
Foxa2 Programs Th2 Cell-Mediated Innate Immunity in the Developing Lung
Chen, G., Wan, H., Luo, F., Zhang, L., Xu, Y. J., Lewkowich, I. P., Wills-Karp, M. A., & Whitsett, J. A. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1000223 · Cited by 96
Targeting IL4/IL4R for the treatment of epithelial cancer metastasis
Venmar, K. T., & Fingleton, B. (2015) · Clinical & Experimental Metastasis · doi:10.1007/s10585-015-9747-9 · Cited by 95
“In normal tissues, the primary binding chain for IL4, IL4 receptor a (IL4Ra) [10, 14], is expressed on T and B lymphocytes, eosinophils, macrophages, endothelial cells, lung fibroblasts, bronchial epithelial cells, MDSCs, and smooth muscle cells [11, 15–20].”
Influential
The immunosuppressive cytokine interleukin-4 increases the clonogenic potential of prostate stem-like cells by activation of STAT6 signalling
Nappo, G., Handle, F., Santer, F. R., McNeill, R. V., Seed, R., Collins, A. T., Morrone, G., Čulig, Z., Maitland, N. J., & Erb, H. H. H. (2017) · Oncogenesis · doi:10.1038/oncsis.2017.23 · Cited by 95
“The activated genes include AKT, p44/42 MAPK, NF-kB, and the JAK/STAT6 pathways, which represents the main mediator of IL-4 signalling in immune cells (19).”
Influential
Cytokine memory of T helper lymphocytes
Löhning, M., Richter, A., & Radbruch, A. (2002) · Advances in immunology · doi:10.1016/s0065-2776(02)80014-1 · Cited by 96
Interleukin-4 induces the activation and collagen production of cultured human intrahepatic fibroblasts via the STAT-6 pathway
Aoudjehane, L., Pissaia, A., Scatton, O., Podevin, P., Massault, P. P., Chouzenoux, S., Soubrane, O., Calmus, Y., & Conti, F. (2008) · Laboratory Investigation · doi:10.1038/labinvest.2008.61 · Cited by 99
“IL-4 exerts its effects by binding to and stimulating its transmembrane receptor (IL-4R), involving the Janus kinases (JAK)-1 and JAK-3, and the signal transducer and activator of transcription (STAT)-6 pathway.(25) In vitro studies have shown that IL-4 can induce fibrosis by activating lung fibroblast proliferation,…”
Background
Anti–interleukin-4 therapy
Steinke, J. W. (2004) · Immunology and Allergy Clinics of North America · doi:10.1016/j.iac.2004.06.008 · Cited by 95
“The phosphorylation of the IL-4Ra cytoplasmic region also provides a docking site for the insulin receptor substrate 1 (IRS-1) and its homolog IRS-2 [33].”
Background
Costimulation, Coinhibition and Cancer
Inman, B. A., Frigola, X., Dong, H., & Kwon, E. D. (2007) · Current Cancer Drug Targets · doi:10.2174/156800907780006878 · Cited by 97
“Interleukin 4 (IL-4) is involved in the differentiation of TH cells into specific subsets, in particular the TH2 subset [81].”
Background
Cutting Edge: STAT6 Serves as a Positive and Negative Regulator of Gene Expression in IL-4-Stimulated B Lymphocytes
Schröder, A., Pavlidis, P., Arimura, A., Capece, D., & Rothman, P. B. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.3.996 · Cited by 96
Transcriptional Regulation of Gata3 in T Helper Cells by the Integrated Activities of Transcription Factors Downstream of the Interleukin-4 Receptor and T Cell Receptor
Scheinman, E. J., & Avni, O. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m807302200 · Cited by 93
Airway and Lung Pathology Due to Mucosal Surface Dehydration in β-Epithelial Na+ Channel-Overexpressing Mice: Role of TNF-α and IL-4Rα Signaling, Influence of Neonatal Development, and Limited Efficacy of Glucocorticoid Treatment
Livraghi-Butrico, A., Grubb, B. R., Hudson, E. J., Wilkinson, K. J., Sheehan, J. K., Mall, M. A., O’Neal, W. K., Boucher, R. C., & Randell, S. H. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0802557 · Cited by 91
“IL-4Rα is a shared component of the receptors for IL-4 and IL-13, two cytokines that trigger Th2-type airway inflammation and remodeling (15,16) and have been highly implicated in the pathogenesis of allergy and asthma (17,18).”
Background
GATA-3 transcriptional imprinting in Th2 lymphocytes: A mathematical model
Höfer, T., Nathansen, H., Löhning, M., Radbruch, A., & Heinrich, R. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.142284699 · Cited by 90
Analysis of γc-Family Cytokine Target Genes
Kovanen, P. E., Rosenwald, A., Fu, J., Hurt, E. M., Lam, L. T., Giltnane, J. M., Wright, G. W., Staudt, L. M., & Leonard, W. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209015200 · Cited by 90
Current and Emerging Strategies to Inhibit Type 2 Inflammation in Atopic Dermatitis
Haddad, E., Cyr, S. L., Arima, K., McDonald, R. A., Levit, N. A., & Nestle, F. O. (2022) · Dermatology and Therapy · doi:10.1007/s13555-022-00737-7 · Cited by 94
“IL-13 binds to IL-13Ra1 and recruits IL-4Ra, forming the type II receptor [39, 88].”
Background
The Role of Interleukin 13 in Classical Hodgkin Lymphoma
Skinnider, B., Kapp, U., & Mak, T. W. (2002) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428190290026259 · Cited by 88
“Signal transduction through the Type II IL-4R occurs primarily via the IL-4Ra chain [25].”
Background
Regulation of Chemokine Expression by Antiinflammatory Cytokines
Hamilton, T. A., Ohmori, Y., & Tebo, J. M. (2002) · Immunologic Research · doi:10.1385/ir:25:3:229 · Cited by 92
Moderate exercise may attenuate some aspects of immunosenescence
Drela, N., Kozdroń, E., & Szczypiorski, P. (2004) · BMC Geriatrics · doi:10.1186/1471-2318-4-8 · Cited by 89
“IL-2, IL-4 and IFN-γ are multifunctional cytokines involved in the development and effectors functions regulation of T, B and NK cells [26-28].”
Background
Stat6 and IRS-2 Cooperate in Interleukin 4 (IL-4)-Induced Proliferation and Differentiation but Are Dispensable for IL-4-Dependent Rescue from Apoptosis
Wurster, A. L., Withers, D. J., Uchida, T., White, M. F., & Grusby, M. J. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.1.117-126.2002 · Cited by 88
“Deletion and mutagenesis studies of the human IL-4R chain in transfected cell lines has led to the functional categorization of the phosphotyrosine residues in the IL-4R chain cytoplasmic tail (24).”
Background
IL-4-mediated inhibition of IFN- production by CD4+ T cells proceeds by several developmentally regulated mechanisms
Wurtz, O. (2004) · International Immunology · doi:10.1093/intimm/dxh050 · Cited by 90
“Alternatively, partial inhibition may reflect a proliferative or survival defect of STAT6-deficient Th1 cells when deprived of IL-12 ( 26 ).”
Background
Interleukin-4– and Interleukin-13–Enhanced Transforming Growth Factor- β 2 Production in Cultured Human Bronchial Epithelial Cells Is Attenuated by Interferon- γ
Wen, F., Kohyama, T., Liu, X., Zhu, Y. K., Wang, H., Kim, H. J., Kobayashi, T., Abe, S., Spurzem, J. R., & Rennard, S. I. (2002) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/ajrcmb.26.4.4784 · Cited by 89
“Both IL-4 and IL-13 interact with specific receptors which are capable of activating several signal transduction pathways leading to altered gene expression (38).”
Background
IL-13 and IL-4 promote TARC release in human airway smooth muscle cells: role of IL-4 receptor genotype
Faffe, D. S., Whitehead, T. R., Moore, P. E., Baraldo, S., Flynt, L., Bourgeois, K., Panettieri, R. A., & Shore, S. A. (2003) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00120.2003 · Cited by 89
“The I4R motif of the IL-4R is also required for insulin receptor substrate binding and subsequent ERK phosphorylation (29).”
Cytokines and Chemokines in HBV Infection
Zhong, S., Zhang, T., Tang, L., & Li, Y. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.805625 · Cited by 90
“Interleukin-4 IL-4 is distinguished as a T helper (Th)2 cytokine that tilts the adaptive response toward humoral immunity by motivating proliferation, differentiation, and antibodies production of B cells, promoting Th2 cells differentiation from naïve CD4 T cells and inhibiting Th1 responses as well as IFN-γ producti…”
Background
Macrophages: Subtypes, Distribution, Polarization, Immunomodulatory Functions, and Therapeutics
Peng, M., Li, N., Wang, H., Li, Y., Liu, H., Luo, Y., Lang, B., Zhang, W., Li, S., Tian, L., et al. (2025) · MedComm · doi:10.1002/mco2.70304 · Cited by 98
“…Type I receptors, which bind only IL-4 and are composed of IL-4R α and γ c subunits (the latter also acts as a subunit in IL-2, IL-7, IL-9, IL-15, and IL-21 receptor complexes); and Type II receptors, which can bind both IL-4 and IL-13 and are composed of IL-4R α and IL-13R α 1 subunits [125, 126].”
Opportunistic Infection-Associated Immune Reconstitution Syndrome in Transplant Recipients
Sun, H., & Singh, N. (2011) · Clinical Infectious Diseases · doi:10.1093/cid/cir276 · Cited by 88
“Th2 cells secrete mainly interleukin (IL)-4 and IL-10, leading to anti-inflammatory and immunosuppressive responses [4, 5].”
CD8 T Cell-Specific Downregulation of Histone Hyperacetylation and Gene Activation of the IL-4 Gene Locus by ROG, Repressor of GATA
Omori, M., Yamashita, M., Inami, M., Ukai‐Tadenuma, M., Kimura, M. Y., Nigo, Y., Hosokawa, H., Hasegawa, A., Taniguchi, M., & Nakayama, T. (2003) · Immunity · doi:10.1016/s1074-7613(03)00210-3 · Cited by 87
IL‐4 induces expression of TARC/CCL17 via two STAT6 binding sites
Wirnsberger, G., Hebenstreit, D., Posselt, G., Horejs‐Hoeck, J., & Duschl, A. (2006) · European Journal of Immunology · doi:10.1002/eji.200635972 · Cited by 89
Interleukins-4, -5, and -13: emerging therapeutic targets in allergic disease
Foster, P. S., Martinez-Moczygemba, M., Huston, D. P., & Corry, D. B. (2002) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(02)00220-6 · Cited by 87
IL4 Receptor ILR4α Regulates Metastatic Colonization by Mammary Tumors through Multiple Signaling Pathways
Venmar, K. T., Carter, K. J., Hwang, D. G., Dozier, E. A., & Fingleton, B. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0093 · Cited by 86
“Activated Akt [9] and Stat6 [5, 10, 11] are known regulators of proliferation and survival.”
BackgroundResultInfluential
IFN-γ and IFN-α Posttranscriptionally Down-Regulate the IL-4-Induced IL-4 Receptor Gene Expression
So, E. Y., Park, H.-H., & Lee, C. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.10.5472 · Cited by 86
“IL-4-responsive element (IL-4RE) (11) sequence (FceRIIb IFN-g-activated site (GAS) (12): 59-GGGTGAATTTCTAAGAAAGGG-39) was labeled using [a-32P]dCTP and Klenow, and the binding reaction with the nuclear extract was performed in the buffer containing 10 mM Tris-Cl (pH 7.5), 50 mM NaCl, 10 mM MgCl2, 1 mM DTT, 1 mM EDTA,…”
BackgroundMethodInfluential
Intracrine Cysteinyl Leukotriene Receptor–mediated Signaling of Eosinophil Vesicular Transport–mediated Interleukin-4 Secretion
Bandeira‐Melo, C., Woods, L. J., Phoofolo, M., & Weller, P. F. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20020516 · Cited by 86
“The actions of IL-4 are not limited to the initiation of Th2 responses, but may also stimulate other cellular responses that contribute to manifestations of allergic diseases (12, 13).”
Background
Cytokine-Mediated Immunopathogenesis of Hepatitis B Virus Infections
Li, X., Liu, X., Tian, L., & Chen, Y. (2016) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-014-8465-4 · Cited by 104
Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines
Junttila, I., Creusot, R. J., Moraga, I., Bates, D. L., Wong, M. T., Alonso, M. N., Suhoski, M. M., Lupardus, P. J., Meier‐Schellersheim, M., Engleman, E. G., et al. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.1096 · Cited by 85
Macrophages and Inflammation
Lee, C., & Choi, E. Y. (2018) · Journal of Rheumatic Diseases · doi:10.4078/jrd.2018.25.1.11 · Cited by 92
Involvement of IL-4, IL-13 and Their Receptors in Pancreatic Cancer
Shi, J., Song, X., Traub, B., Luxenhofer, M., & Kornmann, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22062998 · Cited by 85
“The multiple functions of IL-4 are ini iated through the binding of IL-4 to its respective transfer membrane receptor chain (Figure 2), IL-4-receptor (IL-4R), in both the type I receptor complex, comprising of IL-4-receptor alpha (IL-4Rα) and the co on g mma chain (γc) (IL-4/IL-4Rα/γc) [41], predominantly expressed on…”
BackgroundInfluential

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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