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
Functional Characterization of Human Cysteinyl Leukotriene 1 Receptor Gene Structure
Woszczek, G., Pawliczak, R., Qi, H., Nagineni, S., Alsaaty, S., Logun, C., & Shelhamer, J. H. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.8.5152 · Cited by 56
“The primary pathway of IL-4R signaling relates to the activation of cytoplasmic Janus kinases and the subsequent phosphorylation of several molecules, in particular STAT6, which dimerizes and is translocated to nucleus (26).”
Background
Dual Roles for IFN-γ, But Not for IL-4, in Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice
Yu, S., Sharp, G. C., & Braley‐Mullen, H. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.7.3999 · Cited by 56
“IFNis apparently important for the spontaneous production of autoantibodies, because the production of MTg-specific IgG1 and IgG2b autoantibodies was markedly reduced in IFN- / mice.”
Influential
IL-4 induces serine phosphorylation of the STAT6 transactivation domain in B lymphocytes
Wick, K. R., & Berton, M. T. (2000) · Molecular Immunology · doi:10.1016/s0161-5890(00)00088-2 · Cited by 57
Emerging Biologic Therapies for the Treatment of Atopic Dermatitis
Alvarenga, J. M., Bieber, T. R. M., & Torres, T. R. (2024) · Drugs · doi:10.1007/s40265-024-02095-4 · Cited by 62
Absence of an association of tumor necrosis factor (TNF)-alpha G308A, interleukin-6 (IL-6) G174C and interleukin-10 (IL-10) G1082A polymorphism in women with preeclampsia
Stonek, F., Hafner, E., Metzenbauer, M., Schuchter, K., Stümpflen, I., Schneeberger, C., Zeisler, H., Husslein, P. W., & Philipp, K. (2007) · Journal of Reproductive Immunology · doi:10.1016/j.jri.2007.04.003 · Cited by 55
IL4 receptor α mediates enhanced glucose and glutamine metabolism to support breast cancer growth
Venmar, K. T., Kimmel, D. W., Cliffel, D. E., & Fingleton, B. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.02.020 · Cited by 55
“The Th2 immune cytokine, interluekin-4 (IL4), is known to induce lymphocyte activation and differentiation, and regulate increased lymphocyte proliferation and survival through the type I IL4 receptor (IL4R) [3].”
Background
ICOS-Mediated Costimulation on Th2 Differentiation Is Achieved by the Enhancement of IL-4 Receptor-Mediated Signaling
Watanabe, M., Watanabe, S., Hara, Y., Harada, Y., Kubo, M., Tanabe, K., Toma, H., & Abe, R. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.4.1989 · Cited by 57
“It is well known that Stat6 plays a critical role in the IL-4mediated signal, and that its phosphorylation reflects the strength of IL-4R signaling (2, 3, 27).”
Background
Regulation of Th2 Cell Development by Polycomb Group Gene bmi-1 through the Stabilization of GATA3
Hosokawa, H., Kimura, M. Y., Shinnakasu, R., Suzuki, A., Miki, T., Koseki, H., van Lohuizen, M., Yamashita, M., & Nakayama, T. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.11.7656 · Cited by 56
The role of interleukin‐4 in rheumatic diseases
Dong, C., Fu, T., Ji, J., Li, Z., & Gu, Z. (2018) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.12946 · Cited by 56
The role of Interleukin-4 in COVID-19 associated male infertility – A hypothesis
Renu, K., Subramaniam, M. D., Chakraborty, R., Myakala, H., Iyer, M., Bharathi, G., Siva, K., Vellingiri, B., & Gopalakrishnan, A. V. (2020) · Journal of Reproductive Immunology · doi:10.1016/j.jri.2020.103213 · Cited by 55
Early Exposure to IL-4 Stabilizes IL-4 mRNA in CD4+ T Cells via RNA-Binding Protein HuR
Yarovinsky, T. O., Butler, N. S., Monick, M. M., & Hunninghake, G. W. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.7.4426 · Cited by 56
“By acting through activation of transcription factor STAT6, IL-4 exerts a positive feedback regulation of Th2 differentiation and Il4 gene expression (3).”
Background
Identification of Cellular Intermediates and Molecular Pathways Induced by IL-21 in Human B Cells
Konforte, D., & Paige, C. J. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.12.8381 · Cited by 55
Cytokines that Modulate the Differentiation of Th17 Cells in Autoimmune Uveitis
Guo, K., & Zhang, X. (2021) · Journal of Immunology Research · doi:10.1155/2021/6693542 · Cited by 59
“Type II IL-4R is formed by the IL-4Rα chain and the IL-13Rα1 chain, which shares with the IL-13 receptor and expresses on the surface of nonhematopoietic cells and myeloid cells [152].”
Background
Crosstalk between extracellular vesicles and tumor-associated macrophage in the tumor microenvironment
Chen, Q. Y., Gao, B., Tong, D., & Huang, C. (2022) · Cancer Letters · doi:10.1016/j.canlet.2022.215979 · Cited by 57
IL-4 Is a Critical Determinant in the Generation of Allergic Inflammation Initiated by a Constitutively Active Stat6
Sehra, S., Bruns, H. A., Ahyi, A.-N. N., Nguyen, E., Schmidt, N. W., Michels, E. G., von Bülow, G.-U., & Kaplan, M. H. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.5.3551 · Cited by 54
“In addition to the Jak-Stat pathway, insulin receptor substrate (IRS)(2) and activators of the Ras/ MAPK pathway are recruited to the receptor (17), though some pathways are activated in a cell type specific manner.”
Background
C-Reactive Protein Directly Suppresses Th1 Cell Differentiation and Alleviates Experimental Autoimmune Encephalomyelitis
Zhang, L., Liu, S., Wright, T. T., Shen, Z.-Y., Li, H., Zhu, W., Potempa, L. A., Ji, S., Szalai, A. J., & Wu, Y. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1402909 · Cited by 54
“Accordingly, we found that CRP treatment suppressed phosphorylation of STAT4 and STAT1 downstream of IL-12 signaling (38) whereas it augmented phosphorylation of STAT6 evoked by IL-4 (39) (Fig.”
Background
Amelioration of Experimental Autoimmune Encephalomyelitis by β-elemene Treatment is Associated with Th17 and Treg Cell Balance
Zhang, R., Tian, A., Zhang, H., Zhou, Z., Yu, H., & Chen, L. (2011) · Journal of Molecular Neuroscience · doi:10.1007/s12031-010-9483-1 · Cited by 55
“It is well known that IL-12 (signaling through T-bet and STAT-4) regulates Th1 (Gately et al. 1998), while IL-4 (signaling through STAT-6 and GATA-3) regulates Th2 differentiation ( Nelms et al. 1999 ), transforming growth factor beta (TGF-β) has usually been associated with the development of Treg cells (Chen et al.…”
Background
Global analysis of the eukaryotic pathways and networks regulated by Salmonella typhimurium in mouse intestinal infection in vivo
Liu, X., Lu, R., Xia, Y., & Sun, J. (2010) · BMC Genomics · doi:10.1186/1471-2164-11-722 · Cited by 54
“IL-4 plays a critical role in the regulation of immune responses [97] and the pathogenesis of inflammatory bowel disease [98,99].”
Background
Multifactor dimensionality reduction reveals gene–gene interactions associated with multiple sclerosis susceptibility in African Americans
Brassat, D., Motsinger, A. A., Caillier, S., Erlich, H., Walker, K., Steiner, L., Cree, B., Barcellos, L., Pericak-Vance, M., Schmidt, S., et al. (2006) · Genes and Immunity · doi:10.1038/sj.gene.6364299 · Cited by 54
Opposing Regulation of the Tight Junction Protein Claudin-2 by Interferon-γ and Interleukin-4
Wisner, D. M., Harris, L., Green, C., & Poritz, L. S. (2007) · Journal of Surgical Research · doi:10.1016/j.jss.2007.03.059 · Cited by 54
The role of the p38 pathway in adaptive immunity.
Cook, R., Wu, C.-C., Kang, Y. J., & Han, J. (2007) · PubMed · Cited by 54
Interleukin (IL)-4-independent Maintenance of Histone Modification of the IL-4 Gene Loci in Memory Th2 Cells
Yamashita, M., Shinnakasu, R., Nigo, Y., Kimura, M. Y., Hasegawa, A., Taniguchi, M., & Nakayama, T. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405989200 · Cited by 54
Regulation of T helper type 2 cell differentiation by murine Schnurri-2
Kimura, M. Y., Hosokawa, H., Yamashita, M., Hasegawa, A., Iwamura, C., Watarai, H., Taniguchi, M., Takagi, T., Ishii, S., & Nakayama, T. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20040733 · Cited by 55
Massively parallel knock-in engineering of human T cells
Dai, X., Park, J. J.-Y., Du, Y., Na, Z., Lam, S. Z., Chow, R. D.-W., Renauer, P. A., Gu, J., Shan, X., Chu, Z., et al. (2023) · Nature Biotechnology · doi:10.1038/s41587-022-01639-x · Cited by 56
Endogenously Produced IL-4 Nonredundantly Stimulates CD8+ T Cell Proliferation
Morris, S. C., Heidorn, S. M., Herbert, D. R., Perkins, C. L., Hildeman, D. A., Khodoun, M. V., & Finkelman, F. D. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.182.3.1429 · Cited by 53
“In contrast, although IL-4 binds to a constitutively expressed receptor on T cells that includes c (9) and is known to promote T cell survival, it fails to directly stimulate T cell proliferation in vitro (10, 11), and relatively little is known about its role in T cell homeostasis and expansion in vivo.”
Background
Crosstalk between PKCζ and the IL4/Stat6 pathway during T‐cell‐mediated hepatitis
Durán, Á., Rodríguez, A., Martı́n, P., Serrano, M., Flores, J. M., Leitges, M., Díaz-Meco, M. T., & Moscat, J. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600468 · Cited by 53
“The other arm of the IL-4 signaling pathway involves the insulin receptor substrate (IRS) family of PTB-containing adapters that orchestrate the signaling pathways, culminating in the activation of PI 3-kinase/Akt and Ras/ERK cascades (Nelms et al, 1999; Kelly-Welch et al, 2003).”
Redirection of B cell responsiveness by transforming growth factor β receptor
Roes, J., Choi, B. K., & Cazac, B. B. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0731875100 · Cited by 53
Nuclear Translocation of Cell Adhesion Kinase .BETA./Proline-rich Tyrosine Kinase 2.
Aoto, H., Sasaki, H., Ishino, M., & Sasaki, T. (2002) · Cell Structure and Function · doi:10.1247/csf.27.47 · Cited by 53
“We can refer to the STAT-family and the Smadfamily of transcription factors as examples of regulation of nuclear translocation by protein assembly, wherein homo- and hetero-dimerization take place (Nelms et al., 1999; Massague, 1998).”
Method
Update on the Treatment of Chronic Spontaneous Urticaria
Kolkhir, P., Fok, J. S., Kocatürk, E., Li, P. H., Okas, T.-L., Marcelino, J. L. A., & Metz, M. (2025) · Drugs · doi:10.1007/s40265-025-02170-4 · Cited by 52
“IL-4 also determines the B cell switch towards IgE and IgG4 production [28, 30] and promotes IL-13 production and degranulation of MC [24, 31].”
CCL23 Expression Is Induced by IL-4 in a STAT6-Dependent Fashion
Novak, H., Müller, A., Harrer, N. E., Günther, C., Carballido, J. M., & Woisetschläger, M. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.7.4335 · Cited by 52
“A major constituent of the IL-4 signal transduction pathway is STAT6 (19, 20).”
Background
Activation of c‐Jun‐N‐terminal kinase is critical in mediating lipopolysaccharide‐induced changes in the rat hippocampus
Barry, C. E., Nolan, Y. M., Clarke, R. M., Lynch, A. M., & Lynch, M. A. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.03011.x · Cited by 52
Docking proteins
Brummer, T., Schmitz‐Peiffer, C., & Daly, R. J. (2010) · FEBS Journal · doi:10.1111/j.1742-4658.2010.07865.x · Cited by 62
Lectin activities of cytokines: functions and putative carbohydrate-recognition domains
Cebo, C. (2002) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/s0304-4165(02)00323-9 · Cited by 53
IL4 receptor targeting enables nab-paclitaxel to enhance reprogramming of M2-type macrophages into M1-like phenotype via ROS-HMGB1-TLR4 axis and inhibition of tumor growth and metastasis
Vadevoo, S. M. P., Kang, Y., Gunassekaran, G. R., Lee, S.-M., Park, M.-S., Jo, D. G., Kim, S.-K., Lee, H., Kim, W. J., & Lee, B.-H. (2024) · Theranostics · doi:10.7150/thno.92672 · Cited by 54
Current understanding of Th2 cell differentiation and function
Li, Z., Zhang, Y., & Sun, B. (2011) · Protein & Cell · doi:10.1007/s13238-011-1083-5 · Cited by 57
“IL-4 has antiapoptotic activity on B cells (Liu et al., 1989; Nelms et al., 1999; Wurster et al., 2002), which may be particularly crucial in GCs, as GC B cells are extremely susceptible to apoptosis (Liu et al., 1989).”
Background
Dietary apigenin attenuates the development of atopic dermatitis-like skin lesions in NC/Nga mice
Yano, S., Umeda, D., Yamashita, S., Yamada, K., & Tachibana, H. (2008) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2008.08.002 · Cited by 50
“Furthermore, IgG1 and IgE are commonly induced by CD40 ligand and IL-4 through the STAT6 activation [12,26].”
Background
Integration of IL-2 and IL-4 signals coordinates divergent regulatory T cell responses and drives therapeutic efficacy
Zhou, J. Y., Álvarez‐González, C. A., & Cobb, B. A. (2021) · eLife · doi:10.7554/elife.57417 · Cited by 50
Comparison of Adjuvant Efficacy of Herpes Simplex Virus Type 1 Recombinant Viruses Expressing TH1 and TH2 Cytokine Genes
Osorio, Y., & Ghiasi, H. (2003) · Journal of Virology · doi:10.1128/jvi.77.10.5774-5783.2003 · Cited by 51
“TH1 cells produce both IL-2 and IFN- and are involved in the activation of macrophages, delayed-type hypersensitivity, and production of IgG2a antibody (1, 33).”
ResultInfluential
IL-4 synergistically enhances both IL-2– and IL-12–induced IFN-γ expression in murine NK cells
Bream, J. H., Curiel, R. E., Yu, C., Egwuagu, C. E., Grusby, M. J., Aune, T. M., & Young, H. A. (2003) · Blood · doi:10.1182/blood-2002-08-2602 · Cited by 50
RETRACTED: Silencing of B Cell Receptor Signals in Human Naive B Cells
Feldhahn, N., Schwering, I., Lee, S., Wartenberg, M., Klein, F., Wang, H., Zhou, G., Wang, S. M., Rowley, J. D., Hescheler, J., et al. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20020881 · Cited by 51
“Another PTP, encoded by the PTEN gene, inhibits the activation of BTK in B cells (38), is frequently inactivated by somatic mutation in advanced malignancies resulting in uninhibited PTK activity and expressed at higher levels in naive than (post) GC B cells (Fig.”
Background
Retracted
Comparison of supplementation of n-3 fatty acids from fish and flax oil on cytokine gene expression and growth of milk-fed Holstein calves
Karcher, E., Hill, T. M., Bateman, H. G., Schlotterbeck, R. L., Vito, N., Sordillo, L. M., & VandeHaar, M. J. (2014) · Journal of Dairy Science · doi:10.3168/jds.2013-7160 · Cited by 50
“Interleukin-4 is involved with the regulation of the differentiation of antigen-stimulated naïve T-cells and promotes the production of antiinflammatory cytokines from these cells (Nelms et al., 1999).”
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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