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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BackgroundInfluential
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“In B cells, IL4 stimulates several intracellular signaling pathways including STAT6,(36) which becomes recruited to the IL4R where it is phosphorylated by JAK kinases.(37) The phosphorylated STAT6 forms dimers and translocates to the nucleus to bind DNA and activate transcription of target genes inhibiting apoptosis i…”
Background
Cytokines and cytokine receptors
O’Shea, J. J., Tato, C. M., & Siegel, R. M. (2008) · Elsevier eBooks · doi:10.1016/b978-0-323-04404-2.10010-7 · Cited by 16
Loss of Interleukin-13-Receptor-Alpha-1 Induces Apoptosis and Promotes EMT in Pancreatic Cancer
Shi, J., Shen, X., Kang, Q., Yang, X., Denzinger, M., Kornmann, M., & Traub, B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073659 · Cited by 15
“In our present study, we can confirm the involvement of STAT3, STAT6, PI3K, Akt and ERK1/2 in the response to exogenous IL-4 and IL-13.”
Background
T-helper 2 mechanisms involved in human rhinovirus infections and asthma
Price, A. S., & Kennedy, J. L. (2022) · Annals of Allergy Asthma & Immunology · doi:10.1016/j.anai.2022.08.015 · Cited by 16
The Role of Peritoneal Immunity in Peritoneal Endometriosis and Related Infertility
Huang, Q., Yu, Y., Xu, W., Li, S., Zhou, Y., & Shu, J. (2023) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2808166 · Cited by 19
“IL-4 is a pleiotropic cytokine produced by Th2 cells [131].”
Background
Ultra-Deep Sequencing Reveals the Mutational Landscape of Classical Hodgkin Lymphoma
Gomez, F., Fisk, B. A., McMichael, J. F., Mosior, M., Foltz, J. A., Skidmore, Z. L., Duncavage, E. J., Miller, C. A., Abel, H., Li, Y.-S., et al. (2023) · Cancer Research Communications · doi:10.1158/2767-9764.crc-23-0140 · Cited by 18
Interleukin-4 Alters Early Phagosome Phenotype by Modulating Class I PI3K Dependent Lipid Remodeling and Protein Recruitment
de Keijzer, S., Meddens, M. B. M., Kilic, D., Joosten, B., Reinieren-Beeren, I., Lidke, D. S., & Cambi, A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022328 · Cited by 16
“Among these signals is the type I cytokine Interleukin 4 (IL-4), mainly produced by T helper 2 cells and mast cells and involved in a variety of (patho)physiological events ranging from tissue adhesion and inflammation, to specificity of immunoglobulin class switching and the regulation of immune responses to allergen…”
Cd4+ T-cell-dependent Goblet Cell Proliferation and Expulsion of Gymnophalloides seoi from the Intestine of C57bl/6 Mice
Guk, S.-M., Lee, J.-H., Kim, H.-J., Kim, W.-H., Shin, E., & Chai, J.-Y. (2009) · Journal of Parasitology · doi:10.1645/ge-1807.1 · Cited by 16
The innate antiviral response upregulates IL-13 receptor α2 in bronchial fibroblasts
Campbell-Harding, G., Sawkins, H., Bedke, N., Holgate, S. T., Davies, D. E., & Andrews, A.-L. (2012) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2012.08.030 · Cited by 16
Identification of Novel STAT6-Regulated Proteins in Mouse B Cells by Comparative Transcriptome and Proteome Analysis
Mokada‐Gopal, L., Böser, A., Lehmann, C. H. K., Drepper, F., Dudziak, D., Warscheid, B., & Voehringer, D. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601838 · Cited by 16
“which both contain the IL-4R a-chain (IL-4Ra) (1).”
Background
DNA methylation alterations and their potential influence on macrophage in periodontitis
Jiang, Y., Fu, J., Du, J., Luo, Z., Guo, L., Xu, J., & Liu, Y. F. (2020) · Oral Diseases · doi:10.1111/odi.13654 · Cited by 16
Pharmacological Mechanisms Underlying the Anti-asthmatic Effects of Modified Guomin Decoction Determined by Network Pharmacology and Molecular Docking
Wang, G., Zhou, B., Wang, Z., Meng, Y., Liu, Y., Yao, X., & Feng, C. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.644561 · Cited by 16
Role of IL ‐4 R α during acute schistosomiasis in mice
Ndlovu, H., & Brombacher, F. (2013) · Parasite Immunology · doi:10.1111/pim.12080 · Cited by 17
Neither interleukin‐4 receptor α expression on CD4+ T cells, or macrophages and neutrophils is required for protective immunity to Trichinella spiralis
Michels, C., Scales, H. E., Saunders, K. A., McGowan, S. J., Brombracher, F., Alexander, J. K., & Lawrence, C. E. (2008) · Immunology · doi:10.1111/j.1365-2567.2008.02987.x · Cited by 16
B cells require “nurturing” by CD4 T cells during development in order to respond in chronic graft-versus-host model of systemic lupus erythematosus
Choudhury, A., Cohen, P. L., & Eisenberg, R. A. (2010) · Clinical Immunology · doi:10.1016/j.clim.2010.03.003 · Cited by 16
“B-cell functions indirectly through its effects on T cells, mast cells, macrophages and dendritic cells [27].”
Background
The role of the T-cell costimulatory molecule Tim-1 in the immune response
Curtiss, M. L., & Colgan, J. D. (2007) · Immunologic Research · doi:10.1007/s12026-007-0063-6 · Cited by 16
“which induces specific signal transduction pathways that influence gene expression and cell growth [3–5].”
Background
Aspergillus fumigatus promotes T helper type 2 responses through thymic stromal lymphopoietin production by human corneal epithelial cells
Wang, L., Wang, L., & Wu, X. (2016) · Clinical and Experimental Ophthalmology · doi:10.1111/ceo.12706 · Cited by 16
“We surmised that this phenomenon may be related to IL-4, a potent IgG class switch factor.(47) IL-4 plays a central role in polyclonal B-cell activation.”
Background
Association of IL4 and IL4R polymorphisms with multiple sclerosis susceptibility in Caucasian population: A meta-analysis
Zhang, Z., Wang, L., Sun, X. Y., Zhang, L., & Lu, L.-Y. (2016) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2016.02.049 · Cited by 16
TGFβ C-509T, TGFβ T869C, XRCC1 Arg194Trp, IKBα C642T, IL4 C-590T Genetic polymorphisms combined with socio-economic, lifestyle, diet factors and gastric cancer risk: A case control study in South Indian population
Pavithra, D., Majumdar, G., Rama, R., Swaminathan, R., Gopisetty, G., Ramakrishnan, A., & Rajkumar, T. (2018) · Cancer Epidemiology · doi:10.1016/j.canep.2018.01.004 · Cited by 16
Identification of novel Stat6 regulated proteins in IL‐4‐treated mouse lymphocytes
Tuomela, S., Rautajoki, K. J., Moulder, R., Nyman, T. A., & Lahesmaa, R. (2009) · PROTEOMICS · doi:10.1002/pmic.200800161 · Cited by 16
“Dimerized Stat6 complexes translocate into the nucleus, bind to the regulatory regions of responsive genes in a sequence specific manner, and with the help of cofactors regulate target gene transcription [6, 7].”
Background
Lessons from immunology: IL4R directly promotes mammary tumor metastasis
Venmar, K. T., & Fingleton, B. (2014) · OncoImmunology · doi:10.4161/21624011.2014.955373 · Cited by 16
“1A).(1) While most normal epithelial cells do not express IL4Rs, epithelial cancer cells including breast cancer cells upregulate the type II IL4R consisting of the IL4Ra and IL13 receptor a 1 (IL13Ra1) chains (Fig.”
BackgroundInfluential
Cutaneous Mast Cell Receptors
Hide, M., Yanase, Y., & Greaves, M. W. (2007) · Dermatologic Clinics · doi:10.1016/j.det.2007.06.013 · Cited by 16
IGF-1 Potentiation of IL-4-induced CD23/FcεRII Expression in Human B Cells
Kim, J., Park, H.-H., & Lee, C. (2003) · Molecules and Cells · doi:10.1016/s1016-8478(23)13742-3 · Cited by 16
An RNA external guide sequence ribozyme targeting human interleukin-4 receptor α mRNA
Dreyfus, D. H., Matczuk, A., & Fuleihan, R. (2004) · International Immunopharmacology · doi:10.1016/j.intimp.2004.03.012 · Cited by 16
Allergic bronchopulmonary aspergillosis in a patient with cystic fibrosis: diagnostic criteria when the IgE level is less than 500 IU/mL
Knutsen, A. P., Noyes, B. E., Warrier, M. R., & Consolino, J. D. (2005) · Annals of Allergy Asthma & Immunology · doi:10.1016/s1081-1206(10)61177-5 · Cited by 16
Accumulation of Effector CD4 T Cells during Type 2 Immune Responses Is Negatively Regulated by Stat6
King, S. B. S., Knorn, A. M., Ohnmacht, C., & Voehringer, D. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.2.754 · Cited by 16
“Upon binding of IL-4 or IL-13 to their receptors, Stat6 is recruited to the IL-4R subunit and is phosphorylated by the tyrosine kinases Jak1 and Jak3, resulting in homodimer formation and subsequent translocation to the nucleus, where it regulates the expression of numerous genes involved in type 2 immune responses (5…”
Background
CD4 + T Cell Response Correlates with Naturally Acquired Antibodies against Plasmodium vivax Tryptophan-Rich Antigens
Zeeshan, M., Tyagi, K., & Sharma, Y. D. (2015) · Infection and Immunity · doi:10.1128/iai.03095-14 · Cited by 15
“Several studies indicate that IL-4 helps to sustain the growth and prolongs the survival of CD4 T and B cells (38).”
Background
Therapeutic Effect of IL-4 Receptor-Targeting Pro-Apoptotic Peptide (AP1-ELP-KLAK) in Glioblastoma Tumor Model
Sarangthem, V., Yi, A., Kim, Y.-J., Rehemtulla, A., Lee, B.-H., Jeon, Y. H., Singh, T. D., & Park, R. (2021) · International Journal of Nanomedicine · doi:10.2147/ijn.s316388 · Cited by 16
Mathematical Modeling of Proliferative Immune Response Initiated by Interactions Between Classical Antigen-Presenting Cells Under Joint Antagonistic IL-2 and IL-4 Signaling
Atitey, K., & Anchang, B. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.777390 · Cited by 15
“On the other hand, IL-4R binding shows a much slower association rate of IL-4 ligand as well as a longer delay of dissociation rate of IL-4 from IL-4R (Figure 3B).”
BackgroundInfluential
Harnessing IgG Fc glycosylation for clinical benefit
Archer, E. J., González, J. C., Ghosh, D., Mellins, E., & Wang, T. T. (2022) · Current Opinion in Immunology · doi:10.1016/j.coi.2022.102231 · Cited by 15
Gallic acid enhances anti-lymphoma function of anti-CD19 CAR-T cells in vitro and in vivo
Luo, Z., Shi, J., Jiang, Q., Yu, G., Li, X., Yu, Z., Wang, J., & Shi, Y. (2023) · Molecular Biomedicine · doi:10.1186/s43556-023-00122-6 · Cited by 16
“IL-4 can stimulate the rapid activation of JAK3, thereby inducing STAT3 and STAT5 phosphorylation and nuclear migration [30, 31], which results in enhanced T cell activity [23, 32, 33].”
Background
IL-4–STAT6 axis amplifies histamine-induced vascular endothelial dysfunction and hypovolemic shock
Krempski, J. W., Yamani, A. N., Thota, L. N., Marella, S., Ganesan, V., Sharma, A., Kaneshige, A., Bai, L., Zhou, H., Foster, P. S., et al. (2024) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2024.05.009 · Cited by 17
IL-4 gene expression in adventitial layer (fibrous layer) of hepatic ovine and bovine hydatid cysts
Dorosti, Z., Tolouei, S., Khanahmad, H., Jafari, R., Jafaee, F., Sharafi, S. M., & Darani, H. Y. (2014) · Journal of Parasitic Diseases · doi:10.1007/s12639-014-0593-5 · Cited by 15
“Production of interleukin-4 (IL-4) is directing the immune system toward Th2-dependent allergic reactivity (Maggi 1998; Mueller et al. 2002; Nelms et al. 1999).”
Background
Association Between IL-4 Polymorphisms and Risk of Liver Disease
Wu, Z., Qin, W., Zeng, J., Huang, C., Yu, L., & Li, S. (2015) · Medicine · doi:10.1097/md.0000000000001435 · Cited by 15
“I nterleukin-4 (IL-4), a multifunctional pleiotropic cytokinediscovered in the mid-1980s, is one of the most frequently studied cytokines in inflammation-mediated diseases.1 This mediator is mainly produced by activated T helper 2 (Th2) cells, although mast cells, basophils, and eosinophils are also known to secrete I…”
BackgroundInfluential
Proinflammatory cytokine polarization in type 2 diabetes
BAHGAT, M. D. R. M. H. S. D. M. R., & Ibrahim, D. R. (2020) · Central European Journal of Immunology · doi:10.5114/ceji.2020.97904 · Cited by 15
“IL-4 which is secreted also by basophils and mast cells has pleiotropic functions including Th2 differentiation, B-cell proliferation and immunoglobulin class switching [19].”
Background
Immune Modulation Effects of Lactobacillus casei Variety rhamnosus on Enterocytes and Intestinal Stem Cells in a 5-FU-Induced Mucositis Mouse Model
Yeung, C., Chiau, J. C., Cheng, M.-L., Chan, W., Chang, S., Jiang, C., & Lee, H. (2021) · Gastroenterology Research and Practice · doi:10.1155/2021/3068393 · Cited by 15
Development of Colitis in Signal Transducers and Activators of Transcription 6-Deficient T-Cell Receptor α-Deficient Mice
Okuda, Y., Takahashi, I., Kim, J., Ohta, N., Iwatani, K., Iijima, H., Kai, Y., Tamagawa, H., Hiroi, T., Kweon, M., et al. (2003) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63817-5 · Cited by 15
“The phosphorylated STAT6 then forms homodimers, translocates to the nucleus, and binds to the promoter regions of IL-4-responsive genes to initiate the gene expression.(26) From analysis of mice lacking the STAT6 gene it has been concluded that the signal transducer is essential for the biological functions of IL-4, i…”
BackgroundInfluential
The Atlantic salmon interleukin 4/13 receptor family: Structure, tissue distribution and modulation of gene expression
Sequeida, Á., Castillo, A., Cordero, N., Wong, V., Montero, R., Vergara, C., Valenzuela, B., Vargas, D., Valdés, N., Morales, J., et al. (2019) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2019.11.030 · Cited by 15
Transgenic Expression of Insulin Receptor Substrate 2 in Murine B Cells Alters the Cell Density-Dependence of IgE Production In Vitro and Enhances IgE Production In Vivo
Kelly-Welch, A. E., Wang, H. Y., Wang, L.-M., Pierce, J. H., Jay, G., Finkelman, F. D., & Keegan, A. D. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.5.2803 · Cited by 15
“Because IRS2 and several other known signaling proteins dock to phosphorylated Y1 in the IL4R chain (2), it is possible that elevated IRS2 can block available Y1 docking sites thereby inhibiting the recruitment of another signaling molecule involved in B cell growth such as Shc (39).”
BackgroundInfluential
Differential IL-4/Stat6 activities correlate with differential expression of regulatory genes SOCS-1, SHP-1, and PP2A in colon cancer cells
Yuan, Q., Li, P. D., Li, B. H., Yang, X. Z., Xu, S. B., Liu, X. H., Zhou, F. X., & Zhang, W. J. (2008) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-008-0429-8 · Cited by 15
“Interleukin (IL)-4 is a pleiotropic cytokine involved in a variety of cellular functions including Th2 development, cell growth, and proliferation, the induction of resistance to apoptosis amongst many others (Nelms et al. 1999; Ansel et al. 2006).”
BackgroundInfluential
Posttransplant Interleukin-4 Treatment Converts Rat Liver Allograft Tolerance to Rejection
Wang, C., Li, J., Cordoba, S. P., McLeod, D. J., Tran, G. T., Hodgkinson, S. J., Hall, B. M., McCaughan, G. W., & Bishop, G. A. (2005) · Transplantation · doi:10.1097/01.tp.0000161249.20922.16 · Cited by 15
“This finding was unexpected, as IL-4 inhibits development of Th1 T cells and thereby prevents production of the macrophage-activating cytokine interferon- (9, 22).”
Background

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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