The IL-4 receptor: signaling mechanisms and biologic functions
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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Phosphorylation of STAT6 is a key step downstream in the IL-4 cascade that leads to Arg1 expression.
“previous studies have shown that phosphorylation of STAT6 is a key step downstream in the IL-4 cascade that leads to Arg1 expression (49–51).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [50]
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Neuroendocrine Regulation of Immunity
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“STAT6 is a critical signaling molecule activated by IL-13 receptor ligation and is essential for the development of allergen-induced experimental asthm”
BackgroundInterleukins, from 1 to 37, and interferon-γ: Receptors, functions, and roles in diseases
Akdiş, M., Bürgler, S., Crameri, R., Eiwegger, T., Fujita, H., Alcaide, E. G., Klunker, S., Meyer, N., O’Mahony, L., Palomares, Ó., et al. (2011) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2010.11.050 · Cited by 780 · see citing works
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“IL-4 is a multifunctional cytokine produced by T cells, mast cells and basophils that induces the activation and proliferation of B cells, stimulates Ig class switching to IgG 1 and IgE, and prevents apoptosi”
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Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis
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“, insulin receptor substrate (IRS) proteins]; various binding events within specific regions of the IL-4Rα chain correspond to different cellular transcriptional and growth functions (128).”
Innate Lymphoid Cells: Emerging Insights in Development, Lineage Relationships, and Function
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Tuning the Cytokine Responses: An Update on Interleukin (IL)-4 and IL-13 Receptor Complexes
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The Biology of IgE and the Basis of Allergic Disease
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IL-21 Induces Differentiation of Human Naive and Memory B Cells into Antibody-Secreting Plasma Cells
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“In this regard, IL-4 is known to costimulate IgE synthesis by human B cells (48), and also induce the expression of CD23 on mature B cells (50).”
BackgroundConditional deletion of Gata3 shows its essential function in TH1-TH2 responses
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“IL-4, acting through activation of the transcription factor STAT6, is key in T H 2 differentiation in vitro”
BackgroundPD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells
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Signaling and Transcription in T Helper Development
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IL-4 in the brain: a cytokine to remember
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“This contrasts to IL-4, which inhibits plasma cell differentiation (29) and induces CD23 expression on mature B cells (30).”
BackgroundHypernociceptive role of cytokines and chemokines: Targets for analgesic drug development?
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“IL-4 alpha receptor (IL-4Ra) is a unique member of the common-gamma chain (gc) family of receptors (Nelms et al., 1999), with the ability to signal within three different receptor complexes, known as type I and type II receptors (Andrews et al.”
BackgroundEpithelial-mesenchymal interactions in the pathogenesis of asthma
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IL-4 Acts as a Myoblast Recruitment Factor during Mammalian Muscle Growth
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“The receptor for IL-4 consists of the IL-4R subunit and the c subunit in immune cells or IL-13R 1 in nonlymphoid tissues (Nelms et al., 1999).”
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“IL-4 and IL-13 are mainly produced by Th2 cells and basophils and each have heterodimeric receptors (43).”
BackgroundInfluentialInflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells
Prasad, S. B., Mingrino, R., Kaukinen, K., Hayes, K. L., Powell, R. M., MacDonald, T. T., & Collins, J. E. (2005) · Laboratory Investigation · doi:10.1038/labinvest.3700316 · Cited by 493 · see citing works
“54 and the PI3-kinase pathway via recruitment of the insulin receptor substrate family”
BackgroundIL-4 and IL-13 signaling in allergic airway disease
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“Interestingly, although the message for IL-13Rα1 is present in T cells, there is no surface expression of this chain on human or mouse T cells [20].”
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T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis.
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“Ligation of the IL-4 and IL-13 receptor complexes results in signaling via the insulin receptor substrate (IRS)-1 and 2 and STAT-6 pathways (Nelms et al., 1999).”
BackgroundInfluentialInterleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease
Ghoreschi, K., Thomas, P. T., Breit, S., Dugas, M., Mailhammer, R., van Eden, W., van der Zee, R., Biedermann, T., Prinz, J. C., Mack, M., et al. (2002) · Nature Medicine · doi:10.1038/nm804 · Cited by 453 · see citing works
Anaphylaxis: Lessons from mouse models
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B cells responses and cytokine production are regulated by their immune microenvironment
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“The IL-4 receptor (IL-4R) is expressed on diverse cells including hematopoetic, endothelial, epithelial, muscle, fibroblast, hepatocyte, and brain cells [53]; the expression of IL-4R on these widely diverse cells reflects the pleiotropic effects of IL-4.”
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Interleukin-4 and Interleukin-13 Signaling Connections Maps
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IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells
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“IL-4 plays a critical role in Th2 differentiation and immunoglobulin class switching (25) whereas IL-13 is a major effector of allergic inflammation (26).”
BackgroundStructural Biology of Shared Cytokine Receptors
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Cytokines and Chemokines inMycobacterium tuberculosisInfection
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IL-4/IL-13 signaling beyond JAK/STAT
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“Of note, because T and B cells do not respond to IL-13 (24, 25), IL-4R–deficient mice functionally recapitulate IL-4–deficient animals with respect to these subsets while allowing for analysis of the IL-4/GFP response.”
BackgroundInfluentialStat5 Activation Plays a Critical Role in Th2 Differentiation
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Idiopathic pulmonary fibrosis: an epithelial/fibroblastic cross-talk disorder
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“A variety of inhibitors of the IL-4/IL-13 pathway have been reported, such as SOCS-1 (also known as SSI-1) [21]; however, this inhibitor was suggested to prevent activation of STAT and, for example, act on Jak proteins [37].”
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“IL-4Rfi also recruits the docking proteins insulin receptor substrate (IRS)-1/2 via Tyr497 and links to phosphatidylinositol-3 0 kinase and other signal pathways ( 113 ).”
BackgroundRegulation of Inflammation by Adenosine
Haskó, G., & Cronstein, B. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00085 · Cited by 367 · see citing works
“Genetic studies have yet to confirm the role of A3 receptors in governing macrophage function (Nelms et al., 1999).”
BackgroundThe role of Stat5a and Stat5b in signaling by IL-2 family cytokines
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“IL-4 is a critical mediator that promotes di erentiation of T helper precursor (Thp) cells into Th2 cells, while suppressing di erentiation of Thp into Th1 cells (Nelms et al., 1999).”
BackgroundEvolutionary divergence and functions of the human interleukin (IL) gene family
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“All members in this group bind to heterodimeric receptor complexes.(76) IL4 and IL13 share signalling mechanisms through a receptor complex containing the IL4Ra chain.”
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“PI3K and Akt may also be involved in mitogenic signaling in T cells through cell-cycle regulation via E2F (194, 187).”
BackgroundInfluentialRegulation of inflammation by interleukin-4: a review of "alternatives"
Luzina, I. G., Keegan, A. D., Heller, N. M., Rook, G. A. W., Shea-Donohue, T., & Atamas, S. P. (2012) · Journal of Leukocyte Biology · doi:10.1189/jlb.0412214 · Cited by 351 · see citing works
“This mediator is produced mainly by activated T cells but also by mast cells, basophils, and eosinophils [1].”
BackgroundRegulation of the Anti-Inflammatory Cytokines Interleukin-4 and Interleukin-10 during Pregnancy
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Cutting Edge: Stat6-Dependent Substrate Depletion Regulates Nitric Oxide Production
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“IL-4 and IL-13 are pleiotropic cytokines that play major roles in the regulation of T and B cell function as well as controlling macrophage activity (15).”
BackgroundCytokine dysregulation in autism spectrum disorders (ASD): Possible role of the environment
Goines, P. E., & Ashwood, P. (2013) · Neurotoxicology and Teratology · doi:10.1016/j.ntt.2012.07.006 · Cited by 314 · see citing works
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“produced by activated Th2 cells in addition to NKT cells (54, 55), and CD1 / mice are only deficient for NKT cells.”
BackgroundSignificance of Interleukin (IL)-4 and IL-13 in Inflammatory Arthritis
Iwaszko, M., Biały, S., & Bogunia‐Kubik, K. (2021) · Cells · doi:10.3390/cells10113000 · Cited by 312 · see citing works
Signaling mechanisms, interaction partners, and target genes of STAT6
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“The major IL-4 receptor, the type I IL-4 receptor, is composed of the common gamma chain (gc) and the IL-4Ra chain [27].”
BackgroundThe biology of Stat4 and Stat6
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“Stat6 is activated primarily via the ligation of the IL4 receptor (IL-4R) (for review see Nelms et al., 1999).”
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Importance of Cytokines in Murine Allergic Airway Disease and Human Asthma
Finkelman, F. D., Hogan, S. P., Hershey, G. K. K., Rothenberg, M. E., & Wills-Karp, M. A. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0902185 · Cited by 294 · see citing works
“IL-4 and IL-13 stimulate multiple features of asthma (Table I) by binding to the type I and type II IL-4Rs (bound by IL-4) or selectively to the type II IL-4R (bound by IL-13) and inducing IL-4Ra–mediated activation of the transcription factor Stat6 (7).”
Role of cytokines and inflammation in heart function during health and disease
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“org/molecule/query?afcsid=A001263">A001263 ), which is an essential component of both type I and type II IL-4 receptor”
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“The multifunctional cytokine IL-4, known to induce B-cell activation and proliferation, stimulate Ig class switching to IgG1 and IgE and prevent apoptosis (45), is the only cytokine that controls the expression of XBP-1 in the mature B cell.”
BackgroundThe effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis: a review
Xu, J., Yu, L., Liu, F., Wan, L., & Deng, Z. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1222129 · Cited by 268 · see citing works
A method for the generation of standardized qualitative dynamical systems of regulatory networks
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“The PCR cycles used for each cytokine were as follows: IL-13 (33), IL-4 (34), IL-5 (31), IFN- (29), IL-13R 1 (28), IL-13R 2 (30), IL4R 1 (27), c chain (27), and hypoxanthine-guanine phosphoribosyl transferase (HPRT; reference 23).”
BackgroundMethodImmunotherapy of Cytotoxic T Cell–resistant Tumors by T Helper 2 Cells
Mattes, J. E., Hulett, M. D., Xie, W., Hogan, S. P., Rothenberg, M. E., Foster, P. S., & Parish, C. R. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20021683 · Cited by 257 · see citing works
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“Activation of the IL-4 signaling pathway involves the Janus kinase/signal transducer and activator of transcription pathway and the insulin receptor substrate-1/Pi 3-kinase pathway (40).”
BackgroundSignaling pathways in Th2 development
Mowen, K. A., & Glimcher, L. H. (2004) · Immunological Reviews · doi:10.1111/j.0105-2896.2004.00209.x · Cited by 255 · see citing works
“antibody isotype switching to IgE and IgG1, and also serves as a mitogen for B cells (36).”
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Promotion of B Cell Immune Responses via an Alum-Induced Myeloid Cell Population
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“IL-4 is a pleiotropic cytokine involved in regulation of different immunological functions (28), in particular via inducing MHC class II expression on monocytes (38).”
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“The binding of IL-4 to its heterodimeric receptor leads to STAT6 activation, dimerization, nuclear translocation, and binding to specific elements of various IL-4/IL-13-responsive genes (10).”
BackgroundThe Transcription Factor STAT3 Is Required for T Helper 2 Cell Development
Stritesky, G. L., Muthukrishnan, R., Sehra, S., Goswami, R., Pham, D., Travers, J. B., Nguyen, E., Levy, D. E., & Kaplan, M. H. (2011) · Immunity · doi:10.1016/j.immuni.2010.12.013 · Cited by 234 · see citing works
“STAT6 then becomes phosphorylated, dimerizes, and translocates to the nucleus where it can activate transcription of Th2 cell-specific genes (Nelms et al., 1999).”
Stat6 Is Necessary and Sufficient for IL-4’s Role in Th2 Differentiation and Cell Expansion
Zhu, J., Guo, L., Watson, C. J., Hu-Li, J., & Paul, W. E. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.12.7276 · Cited by 301 · see citing works
“Stat6 interacts with the second, third, and fourth conserved tyrosines (Y575, Y603, and Y631) of IL-4Ra (2, 17, 18).”
BackgroundSubnormal Cytokine Profile in the Tear Fluid of Keratoconus Patients
Jun, A. S., Cope, L., Speck, C. L., Feng, X., Lee, S., Meng, H., Hamad, A. R. A., & Chakravarti, S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0016437 · Cited by 231 · see citing works
“Decreased IL-4 in keratoconus may have broad immune and non-immune consequences [17] that should be considered in the context of corneal thinning and abnormal stromal extracellular matrix (ECM).”
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“The alpha subunit of the IL-4 receptor (IL-4Ra) binds with high affinity to IL-4 and is required for IL-4 response and alternative activation of macrophages (Nelms et al., 1999).”
BackgroundDissecting asthma using focused transgenic modeling and functional genomics
Kuperman, D. A., Lewis, C. C., Woodruff, P. G., Rodriguez, M. W., Yang, Y. H., Dolganov, G., Fahy, J. V., & Erle, D. J. (2005) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2005.03.024 · Cited by 220 · see citing works
The Role of the Immune System in the Development of Endometriosis
Abramiuk, M., Grywalska, E., Małkowska, P., Sierawska, O., Hrynkiewicz, R., & Niedźwiedzka‐Rystwej, P. (2022) · Cells · doi:10.3390/cells11132028 · Cited by 231 · see citing works
“Interleukin 4 (IL-4) is a cytokine with pleiotropic activity [111].”
BackgroundColognato, R., Slupsky, J. R., Jendrach, M., Burýšek, L., Syrovets, T., & Simmet, T. (2003) · Blood · doi:10.1182/blood-2002-08-2497 · Cited by 221 · see citing works
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Aithal, G. P., Ramsay, L., Daly, A. K., Sonchit, N., Leathart, J. B. S., Alexander, G., Kenna, J. G., Caldwell, J., & Day, C. P. (2004) · Hepatology · doi:10.1002/hep.20205 · Cited by 216 · see citing works
Growth Factor Independent-1 Induced by IL-4 Regulates Th2 Cell Proliferation
Zhu, J., Guo, L., Min, B., Watson, C. J., Hu‐Li, J., Young, H. A., Tsichlis, P. N., & Paul, W. E. (2002) · Immunity · doi:10.1016/s1074-7613(02)00317-5 · Cited by 217 · see citing works
Whyte, C. S., Bishop, E., Rückerl, D., Gaspar-Pereira, S., Barker, R. N., Allen, J. E., Rees, A. J., & Wilson, H. M. (2011) · Journal of Leukocyte Biology · doi:10.1189/jlb.1110644 · Cited by 216 · see citing works
“IL-4-induced PI3K activity is considered to be highly important for M2 macrophage polarization and especially, arginase I expression [36–38].”
BackgroundCytokine-Induced Modulation of Colorectal Cancer
Mager, L. F., Wasmer, M.-H., Rau, T. T., & Krebs, P. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00096 · Cited by 215 · see citing works
“The type I IL-4 receptor complex is composed of IL-4Rα and the common gamma chain, whereas the type II IL-4 receptor consists of the IL-4Rα and IL-13Rα1 subunits (40).”
BackgroundA Critical Evaluation of Anti-IL-13 and Anti-IL-4 Strategies in Severe Asthma
Bagnasco, D., Ferrando, M., Varricchi, G., Passalacqua, G., & Canonica, G. W. (2016) · International Archives of Allergy and Immunology · doi:10.1159/000447692 · Cited by 213 · see citing works
Bai, A., Hu, H., Yeung, M., & Chen, J. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.12.7632 · Cited by 212 · see citing works
“To confirm this observation, we measured the levels of KLF2 transcript in STAT6 / T cells because STAT6 is required for mediating IL-4R signaling (23).”
BackgroundLiu, W., Taso, O., Wang, R., Bayram, S., Graham, A. C., Garcia-Reitboeck, P., Mallach, A., Andrews, W. D., Piers, T. M., Botia, J. A., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa209 · Cited by 214 · see citing works
Interleukin-4 receptor signaling pathways in asthma pathogenesis
Chatila, T. A. (2004) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2004.08.004 · Cited by 210 · see citing works
Role of IL-13 in regulation of anti-tumor immunity and tumor growth
Terabe, M., Park, J. M., & Berzofsky, J. A. (2003) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-003-0445-0 · Cited by 210 · see citing works
“the receptor components phosphorylate the second, third, or fourth tyrosine residues of the IL-4Ra cytoplasmic domain [50].”
Role of Interleukin-4 in Regulation of Age-related Inflammatory Changes in the Hippocampus
Nolan, Y. M., Maher, F. O., Martin, D. S. D., Clarke, R. M., Brady, M. T., Bolton, A. E., Mills, K. H. G., & Lynch, M. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m412170200 · Cited by 210 · see citing works
Allergic Bronchopulmonary Aspergillosis in Asthma and Cystic Fibrosis
Knutsen, A. P., & Slavin, R. G. (2011) · Clinical and Developmental Immunology · doi:10.1155/2011/843763 · Cited by 209 · see citing works
“IL-4 receptor type II, also known as the IL13 receptor, is formed by the association of IL-4RA with the IL-13RA subunits and is located on immune cells, bronchial epithelium, and vascular endothelium.”
BackgroundGene expression and angiotropism in primary CNS lymphoma
Rubenstein, J. L., Fridlyand, J., Shen, A., Aldape, K. D., Ginzinger, D. G., Batchelor, T. T., TRESELER, P. A., Berger, M. S., McDermott, M., Prados, M. D., et al. (2006) · Blood · doi:10.1182/blood-2005-03-0897 · Cited by 209 · see citing works
“The multifunctional cytokine IL-4, an important regulator of Bcell activation, proliferation, aggregation and survival, is the only cytokine known to regulate expression of XBP-1 in B-cells, and was thus a logical candidate.(24,30,31) This cytokine has also been demonstrated to regulate angiogenesis.”
The Common Cytokine Receptor γ Chain Family of CytokinesPreprint
Lin, J., & Leonard, W. J. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a028449 · Cited by 210 · see citing works
“Thus, there are key roles for STAT1 and STAT5 dimers versus tetramers in mediating cytokine signaling, indicating that targeting the forma- Y392 Y510 Shc Ras SOS Grb2 Raf1 MEK MAPK STAT5 STAT5 STAT5 Akt PI3K p70S6K STAT5 Gene expression Biological responses Rapamycin Nucleus IL-2 STAT5 dimer STAT5 tetramer pY pY pY pY…”
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.
- 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
- 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
- Health Sciences › Medicine › Oncology › 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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