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
Interleukin 4–induced gene 1 is activated in primary mediastinal large B-cell lymphoma
Copie‐Bergman, C., Boulland, M., Dehoulle, C., Möller, P., Farcet, J., Dyer, M. J. S., Haïoun, C., Roméo, P., Gaulard, P., & Leroy, K. (2003) · Blood · doi:10.1182/blood-2002-07-2215 · Cited by 73
Controlling Mast Cell Activation and Homeostasis: Work Influenced by Bill Paul That Continues Today
Caslin, H. L., Kiwanuka, K. N., Haque, T. T., Taruselli, M. T., MacKnight, H. P., Paranjape, A. R., & Ryan, J. J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00868 · Cited by 72
Single-cell transcriptomes and runx2b−/− mutants reveal the genetic signatures of intermuscular bone formation in zebrafish
Nie, C., Wan, S., Chen, Y., Huysseune, A., Wu, Y., Zhou, J., Hilsdorf, A. W. S., Wang, W., Witten, P. E., Lin, Q., et al. (2022) · National Science Review · doi:10.1093/nsr/nwac152 · Cited by 72
Role of IL-4 and Th2 responses in allograft rejection and tolerance
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Selective downregulation of prostaglandin E2–related pathways by the TH2 cytokine IL-13
Trudeau, J. B., HU, H., Chibana, K., Chu, H. W., Westcott, J. Y., & Wenzel, S. E. (2006) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2006.01.049 · Cited by 72
Differential Secretion of Cytokines
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Cytokines and Chemokines—Their Receptors and Their Genes: An Overview
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StarPEG‐Heparin Hydrogels to Protect and Sustainably Deliver IL‐4
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IL-4 Confers NK Stimulatory Capacity to Murine Dendritic Cells: A Signaling Pathway Involving KARAP/DAP12-Triggering Receptor Expressed on Myeloid Cell 2 Molecules
Terme, M., Tomasello, E., Maruyama, K., Crépineau, F., Chaput, N., Flament, C., Marolleau, J., Angevin, E., Wagner, E. F., Salomon, B. L., et al. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.10.5957 · Cited by 72
Regulation of the Dephosphorylation of Stat6
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Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6
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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
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“In the intracellular region, mammalian IL-4Rα has conserved box 1 and box 2 sequences as well as five conserved tyrosine residues that are important for signalling after receptor binding ( Nelms et al. 1999 ).”
BackgroundInfluential
T helper type 2 differentiation and intracellular trafficking of the interleukin 4 receptor-α subunit controlled by the Rac activator Dock2
Tanaka, Y., Hamano, S., Gotoh, K., Murata, Y., Kunisaki, Y., Nishikimi, A., Takii, R., Kawaguchi, M., Inayoshi, A., Masuko, S., et al. (2007) · Nature Immunology · doi:10.1038/ni1506 · Cited by 70
“IL-4R consists of the IL-4R α-chain (IL-4Rα), which binds IL-4 with high affinity, and the common γ-chain, which transmits signals into the cell interior and is also a component of the receptors for IL-2, IL-7, IL-9, IL-15 and IL-21 (refs”
Background
In vivo regulation of the allergic response by the IL-4 receptor α chain immunoreceptor tyrosine-based inhibitory motif
Tachdjian, R., Khatib, S. A., Schwinglshackl, A., Kim, H. S., Chen, A., Blasioli, J., Mathias, C. B., Kim, H. Y., Umetsu, D. T., Oettgen, H. C., et al. (2010) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2010.01.054 · Cited by 71
Interleukin-13 sensitivity and receptor phenotypes of human glial cell lines: non-neoplastic glia and low-grade astrocytoma differ from malignant glioma
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“In lymphocytes, the interleukin-2 (IL2R) c chain is dominant and forms a heterodimer with IL-4Ra [18, 21].”
BackgroundInfluential
Development of a Human IgG4 Bispecific Antibody for Dual Targeting of Interleukin-4 (IL-4) and Interleukin-13 (IL-13) Cytokines
Spiess, C., Bevers, J. J., Jackman, J. K., Chiang, N., Nakamura, G. R., Dillon, M. A., Liu, H., Molina, P., Elliott, J. M., Shatz-Binder, W., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.480483 · Cited by 72
“Interleukin 4 (IL-4) and interleukin 13 (IL-13) are two cytokines that are associated with type 2 inflammation (17) (18) (19) (20) (21).”
Background
IL-4 Suppresses the Expression and the Replication of Hepatitis B Virus in the Hepatocellular Carcinoma Cell Line Hep3B
Lin, S., Shu, P., Chang, C., Ng, A., & Hu, C. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.9.4708 · Cited by 71
“Discussion IL-4, a cytokine produced by Th2 cells, NKT cells, basophils, and mast cells, displays a wide array of immunological functions, ranging from Th2 development, lymphocyte proliferation, and up-regulation of class II MHC expression to IgE class switch (10); it also has a role in asthma, allergy, and resistance…”
Background
IL-4–Stat6 Signaling Induces Tristetraprolin Expression and Inhibits TNF-α Production in Mast Cells
Suzuki, K., Nakajima, H., Ikeda, K., Maezawa, Y., Suto, A., Takatori, H., Saito, Y., & Iwamoto, I. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20031701 · Cited by 70
“Binding of IL-4 to IL-4R results in the activation of signal transducers and activators of transcription 6 (Stat6) and induces the expression of IL-4–inducible genes, including class II major histocompatibility molecules, low-affinity IgE receptor (CD23), and IL-4R chain (12, 13).”
BackgroundInfluential
IL-4-Activated STAT-6 Inhibits IFN-γ-Induced CD40 Gene Expression in Macrophages/Microglia
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Interleukin-4 enhances prostate-specific antigen expression by activation of the androgen receptor and Akt pathway
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“IL-4 has biological effects on many immune cells, including B and T lymphocytes, mast cells, and macrophages, and plays a central role in regulating inflammatory and cell-mediated immune responses (Nelms et al., 1999).”
BackgroundInfluential
Critical Role of Regulator G-Protein Signaling 10 (RGS10) in Modulating Macrophage M1/M2 Activation
Lee, J., Chung, J., Kannarkat, G. T., & Tansey, M. G. (2013) · PLoS ONE · doi:10.1371/journal.pone.0081785 · Cited by 71
“Rgs10-/- macrophages display attenuated mRNA expression of M2 activation markers in response to IL-4 A key mechanism by which the effects of IL-4 or IL-13 are mediated is activation of the STAT6 pathway [17].”
BackgroundInfluential
Interleukin-4 as a therapeutic target
Gärtner, Y., Bitar, L., Zipp, F., & Vogelaar, C. F. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108348 · Cited by 72
Biological implications of glycosaminoglycan interactions with haemopoietic cytokines
Coombe, D. R. (2008) · Immunology and Cell Biology · doi:10.1038/icb.2008.49 · Cited by 70
The Dual Syk/JAK Inhibitor Cerdulatinib Antagonizes B-cell Receptor and Microenvironmental Signaling in Chronic Lymphocytic Leukemia
Blunt, M. D., Koehrer, S., Dobson, R. C., Larráyoz, M., Wilmore, S., Hayman, A., Parnell, J., Smith, L. D., Davies, A. J., Johnson, P., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-1662 · Cited by 70
“kinases JAK1 and JAK3 resulting in phosphorylation of STAT6 (pSTAT6)(15).”
Background
Upregulation of IL-9 and JAK-STAT signaling pathway in children with autism
Ahmad, S. F., Nadeem, A., Ansari, M. A., Bakheet, S. A., AL-Ayadhi, L. Y., & Attia, S. M. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.08.002 · Cited by 70
“IL-4 activates JAK/STAT signaling cascades (Nelms et al., 1999).”
Protective Effect of Interleukin‐4 −589T Polymorphism on Human Immunodeficiency Virus Type 1 Disease Progression: Relationship with Virus Load
Nakayama, E. E., Meyer, L., Iwamoto, A., Persoz, A., Nagai, Y., Rouzioux, C., Delfraissy, J., Debré, P., McIlroy, D., Theodorou, I. D., et al. (2002) · The Journal of Infectious Diseases · doi:10.1086/339825 · Cited by 70
“Interleukin (IL)–4 has multiple immune response–modulating functions, including induction of IgE production in B lymphocytes and the differentiation of precursor T helper (Th) cells toward the Th2 subset that mediates humoral immunity [1].”
Background
Expression of mRNAs for interleukin-4, interleukin-6 and their receptors in porcine corpus luteum during the estrous cycle
Sakumoto, R., Komatsu, T., Kasuya, E., Saito, T., & Okuda, K. (2005) · Domestic Animal Endocrinology · doi:10.1016/j.domaniend.2005.11.001 · Cited by 69
“IL-4 also helps to regulate inflammatory responses [28], which have been proposed to bear similarity to the ovulatory process [29].”
Background
Adversomics: a new paradigm for vaccine safety and design
Whitaker, J. A., Ovsyannikova, I. G., & Poland, G. A. (2015) · Expert Review of Vaccines · doi:10.1586/14760584.2015.1038249 · Cited by 71
“includes the SNP rs2243250 that is associated with augmented secretion of an important Th2-regulatory cytokine, IL-4, known to inhibit IFN-g production and Th1 response [55,56].”
Peptide Nucleic Acids Are Potent Modulators of Endogenous Pre-mRNA Splicing of the Murine Interleukin-5 Receptor-α Chain
Karras, J. G., Maier, M. A., Lü, T., Watt, A. T., & Manoharan, M. (2001) · Biochemistry · doi:10.1021/bi010263l · Cited by 70
DNA Array Analysis of Changes in Preovulatory Gene Expression in the Rat Ovary1
Leo, C. P., Pisarska, M. D., & Hsueh, A. J. W. (2001) · Biology of Reproduction · doi:10.1095/biolreprod65.1.269 · Cited by 69
“In addition, IL-4 has an important role in regulating inflammatory responses [15], which have been proposed to bear similarity to the ovulatory process [3].”
Background
Interleukin-4 and -10 gene polymorphisms and spontaneous preterm birth in multifetal gestations
Kalish, R. B., Vardhana, S. A., Gupta, M., Perni, S. C., & Witkin, S. S. (2004) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2003.09.066 · Cited by 67
Role of biochemical factors in the pathogenesis of keratoconus.
Wojcik, K. A., Błasiak, J., Szaflik, J., & Szaflik, J. P. (2014) · Acta Biochimica Polonica · doi:10.18388/abp.2014_1923 · Cited by 68
“IL-4 is involved in the regulation of cell proliferation and tissue homeostasis (Nelms et al., 1999).”
Background
Regulation of Macrophage, Dendritic Cell, and Microglial Phenotype and Function by the SOCS Proteins
McCormick, S. M., & Heller, N. M. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00549 · Cited by 69
“Given the importance of insulin availability and metabolism in macrophage polarization (101–103) as well as the importance of IRS-1/-2 in IL-4 signaling (104, 105), SOCS6 and SOCS7 may play a yet undefined role in macrophage polarization.”
Background
Interleukin-4-Pseudomonas Exotoxin Chimeric Fusion Protein for Malignant Glioma Therapy
Kawakami, M., Kawakami, K., & Puri, R. K. (2003) · Journal of Neuro-Oncology · doi:10.1023/a:1026294416718 · Cited by 68
Association of the IL4R single‐nucleotide polymorphism I50V with rapidly erosive rheumatoid arthritis
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Immunopathogenesis of allergic bronchopulmonary aspergillosis in cystic fibrosis
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Eosinophils and Macrophages within the Th2-Induced Granuloma: Balancing Killing and Healing in a Tight Space
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“However, these have proved not to be unique to AAMs (126, 127).”
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Deletion of IL-4Rα on CD4 T Cells Renders BALB/c Mice Resistant to Leishmania major Infection
Radwanska, M., Cutler, A. J., Hoving, J. C., Magez, S., Hölscher, C., Bohms, A., Arendse, B., Kirsch, R., Hünig, T., Alexander, J. K., et al. (2007) · PLoS Pathogens · doi:10.1371/journal.ppat.0030068 · Cited by 67
“IL-4 and IL-13 share a common signaling pathway through the IL-4Ra chain [26], and as such the combined role of both cytokines can be studied in vivo in IL-4Ra / mice.”
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IL-4 Regulates Bim Expression and Promotes B Cell Maturation in Synergy with BAFF Conferring Resistance to Cell Death at Negative Selection Checkpoints
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Genome-Wide Analysis Reveals Unique Regulation of Transcription of Th2-Specific Genes by GATA3
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Inhibition of Kit Expression by IL-4 and IL-10 in Murine Mast Cells: Role of STAT6 and Phosphatidylinositol 3′-Kinase
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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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