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Interleukin-4 receptor

The interleukin-4 receptor (IL-4R) is a heterodimeric type I cytokine receptor that specifically binds the pleiotropic cytokine interleukin-4 (IL-4), a glycoprotein with a four alpha-helix bundle structure essential for modulating immune responses, particularly in type 2 immunity.^[1]^[2] IL-4R exists in two primary isoforms: the type I receptor, composed of the IL-4Rα chain and the common gamma chain (γc), predominantly expressed on hematopoietic cells such as T cells, B cells, and mast cells; and the type II receptor, formed by IL-4Rα paired with IL-13Rα1, found on both hematopoietic and non-hematopoietic cells and capable of binding both IL-4 and IL-13.^[1]^[2] Upon ligand binding, IL-4 initially interacts with the extracellular domain of IL-4Rα with high affinity (K_d ≈ 150–266 pM), inducing a conformational change that recruits the secondary chain (γc for type I or IL-13Rα1 for type II) to form the active complex, as revealed by the 2.3 Å crystal structure of the IL-4/IL-4Rα intermediate.^[3]^[2] This assembly activates intracellular Janus kinase (JAK) family members—JAK1 and JAK3 for type I, or JAK1, JAK2, and TYK2 for type II—which phosphorylate and dimerize signal transducer and activator of transcription 6 (STAT6), the primary downstream effector driving gene expression for Th2 cell differentiation, B cell class switching to IgE, and M2 macrophage polarization.^[1]^[2] Additional pathways, including PI3K/Akt for anti-apoptotic effects and MAPK for proliferation, contribute to IL-4R's roles in host defense against parasites, allergic inflammation, and conditions like asthma and atopic dermatitis.^[1]^[2] Therapeutically, targeting IL-4Rα with monoclonal antibodies such as dupilumab inhibits type II signaling, significantly reducing exacerbations in moderate-to-severe asthma (by up to 87%) and improving outcomes in atopic dermatitis by blocking IL-4- and IL-13-mediated inflammation. As of 2025, dupilumab has additional U.S. FDA approvals for chronic obstructive pulmonary disease (2024), chronic spontaneous urticaria, and bullous pemphigoid (both 2025).^[2]^[4]^[5]^[6]

Overview

Definition and Types

The interleukin-4 receptor (IL-4R) is a heterodimeric cell surface receptor complex that specifically binds interleukin-4 (IL-4), a pleiotropic cytokine central to type 2 immune responses, including allergy, asthma, and host defense against parasites.^[2] The receptor shares key structural components with the interleukin-13 (IL-13) receptor system, enabling overlapping signaling in response to these related cytokines.^[7] Originally identified in the late 1980s through studies demonstrating high-affinity binding of IL-4 to T cells and other immune cells, the receptor's alpha chain is encoded by the IL4R gene, located on human chromosome 16p12.1.^[8]^[9] Two primary types of IL-4R have been characterized based on their subunit composition and ligand specificity. The type I IL-4R consists of the IL-4Rα chain paired with the common gamma chain (γc, also designated IL-2Rγ), forming a complex that binds IL-4 with high affinity but does not accommodate IL-13.^[10] This receptor variant is predominantly expressed on hematopoietic cells, such as T cells, B cells, and myeloid lineages, where it mediates IL-4-dependent processes like T helper 2 (Th2) cell differentiation.^[11] In contrast, the type II IL-4R comprises the IL-4Rα chain associated with the IL-13Rα1 chain, allowing it to bind both IL-4 and IL-13 with comparable affinity.^[10] This form is widely expressed on non-hematopoietic cells, including epithelial cells, smooth muscle cells, and fibroblasts, facilitating broader tissue responses to these cytokines.^[9] The IL-4Rα subunit serves as the essential shared component for both receptor types, ensuring specificity in IL-4 binding and initiation of downstream signaling.^[7] Encoded by a single IL4R gene spanning approximately 51 kb with 16 exons, this subunit undergoes alternative splicing to produce multiple isoforms, including membrane-bound and soluble forms that modulate ligand availability.^[12]^[13]

Tissue Expression and Regulation

The interleukin-4 receptor (IL-4R) is expressed on a variety of hematopoietic cells, with particularly high levels observed on T helper 2 (Th2) cells, B cells, mast cells, eosinophils, basophils, monocytes, and macrophages.^[14] The receptor is also present on non-immune cells such as fibroblasts, endothelial cells, smooth muscle cells, epithelial cells, and hepatocytes.^[15] Type I IL-4R, composed of IL-4Rα and the common gamma chain (γc), predominates on hematopoietic cells like T and B cells, whereas Type II IL-4R, which pairs IL-4Rα with IL-13Rα1, is more broadly distributed across non-hematopoietic tissues.^[2] IL-4R exhibits ubiquitous tissue distribution but shows dynamic upregulation at sites of allergic inflammation, such as the airways and skin, where it supports local immune responses.^[16] In the central nervous system, expression is low on resting neurons but can be induced under inflammatory conditions, enabling responsiveness to IL-4 in the brain.^[17] Expression of IL-4R is tightly regulated at multiple levels. Transcriptionally, STAT6 and NF-κB transcription factors control IL4RA gene promoter activity, with IL-4 itself inducing STAT6-dependent upregulation of IL-4Rα on target cells like CD8+ T cells.^[18]^[19] Additionally, a soluble isoform of IL-4Rα, generated by alternative splicing, functions as a decoy receptor that binds IL-4 in the extracellular space, limiting its availability for membrane-bound receptor activation and thus attenuating signaling.^[20]^[21] In aging, expression of the Type I IL-4R declines on T cells, contributing to dysregulated immune responses, while IL-4 signaling via IL-4R in macrophages promotes anti-senescence effects that help maintain tissue homeostasis, as shown in studies up to 2024.^[22] Polymorphisms in the IL4RA gene, such as the I50V variant (rs1805010), influence baseline receptor expression levels and ligand binding efficiency, thereby affecting susceptibility to immune-mediated conditions.^[23]^[24]

Molecular Structure

Subunits and Isoforms

The interleukin-4 receptor (IL-4R) is composed of two main subunits: the IL-4Rα chain, which serves as the primary binding component for IL-4, and either the common gamma chain (γc) or the IL-13Rα1 chain, forming distinct receptor types.^[25] The IL-4Rα subunit is a ~140 kDa transmembrane glycoprotein consisting of 825 amino acids, with an extracellular domain featuring an N-terminal immunoglobulin-like domain followed by two fibronectin type III modules, a single transmembrane helix, and a cytoplasmic tail containing motifs such as the box 1 sequence for Janus kinase (JAK) association.^[26]^[27]^[28]^[29] The common gamma chain (γc), encoded by IL2RG, is a ~64 kDa glycoprotein shared among receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, and it pairs with IL-4Rα to form the type I IL-4R complex, contributing to its structural stability on hematopoietic cells.^[30]^[31] In contrast, the IL-13Rα1 subunit is a ~47 kDa type I transmembrane protein specific to the type II IL-4R, acting as a low-affinity binder for IL-13 while facilitating enhanced IL-4 signaling upon heterodimerization with IL-4Rα, primarily on non-hematopoietic cells.^[32] IL-4Rα exists in two primary isoforms generated by alternative splicing: a full-length membrane-bound form (825 amino acids) that includes the transmembrane and cytoplasmic domains, and a soluble form lacking these regions, which is secreted and functions as a decoy antagonist by binding IL-4 without initiating signaling.^[26]^[33] The soluble isoform is generated by alternative splicing that utilizes exons 1 through 8, encoding the extracellular domain followed by three additional amino acids (Asn-Ile-Cys), and lacks the transmembrane and cytoplasmic domains encoded by exons 9-12, resulting in a secreted ~38 kDa glycoprotein.^[33] Neither the γc nor IL-13Rα1 subunits exhibit significant splice isoforms in humans, though post-translational modifications such as N-linked glycosylation on their extracellular domains can modulate ligand binding affinity. The IL4R gene, located on chromosome 16p12.1, spans approximately 50 kb and comprises 12 exons, with the majority encoding the extracellular domain in the initial exons and the transmembrane/cytoplasmic regions in later ones.^[34] A notable genetic variation is the Q576R polymorphism (rs1801275) in exon 11 of IL4R, which substitutes arginine for glutamine at position 576 in the cytoplasmic tail and has been associated with altered signaling efficiency, particularly in enhancing IRS-2 pathway activation and susceptibility to allergic diseases. The IL-4Rα chain is uniquely shared between type I and type II receptors, enabling overlapping yet distinct responses to IL-4 and IL-13.^[25]

Three-Dimensional Architecture

The interleukin-4 receptor (IL-4R) belongs to the class I cytokine receptor family, featuring an extracellular cytokine-binding homology region (CHR) composed of two fibronectin type III-like domains that include the conserved WSXWS motif essential for maintaining structural integrity and proper folding.^[35]^[26] This motif, located in the membrane-proximal domain, stabilizes the receptor through hydrophobic and hydrophilic interactions that position key residues for assembly.^[36] The core subunit, IL-4Rα, has an extracellular domain whose crystal structure (PDB: 1IAR) displays an L-shaped topology, with the N-terminal D1 domain adopting an immunoglobulin-like fold featuring seven antiparallel β-strands and three disulfide bonds (Cys9–Cys19, Cys29–Cys59, Cys49–Cys61) for stability, while the C-terminal D2 domain forms a fibronectin type III fold with the WSXWS motif (residues 187–191) in a β-bulge preceding the final strand.^[37] The D1 and D2 domains connect via a short linker, resulting in a bent conformation that orients perpendicular to the cytokine's helical axes. The intracellular domain of IL-4Rα spans approximately 557 residues, with the membrane-proximal juxtamembrane region comprising about 50 residues that lack intrinsic kinase activity and instead associate with Janus kinases (JAKs) for signaling initiation.^[38]^[26] Quaternary assembly involves IL-4Rα as the shared component in two complexes: the Type I ternary complex with IL-4 and the common γ-chain (γc), and the Type II ternary complex with IL-4 and IL-13Rα1.^[39] These form asymmetric dimers, with the membrane-proximal interface mediated by D2 domains of the partnering chains burying 1200–1300 Å² through hydrophobic contacts, and IL-4's helix D contributing to a knob-into-hole fit at the primary binding site.^[39] Across mammals, IL-4Rα exhibits strong evolutionary conservation, particularly in the extracellular domain, which shares 51% amino acid identity between human and mouse orthologs.^[40]

Ligand Binding and Receptor Activation

Interaction with Interleukin-4

Interleukin-4 (IL-4), a prototypical four-helix bundle cytokine, binds to the interleukin-4 receptor alpha (IL-4Rα) chain with high affinity through two primary interfaces known as sites I and II on the ligand.^[37] Site I, involving helices A and C of IL-4, forms the initial high-affinity contact with IL-4Rα, while site II, centered on helix D, contributes additional interactions that stabilize the complex.^[37] This binding exhibits a dissociation constant (K_d) of approximately 20–300 pM for the IL-4/IL-4Rα binary complex, reflecting the subnanomolar affinity essential for physiological signaling.^[41] Subsequent recruitment of the common gamma chain (γc) or IL-13 receptor alpha 1 (IL-13Rα1) to site III on IL-4 occurs with lower affinity, enhancing overall avidity in the ternary complex.^[42] The specificity of IL-4Rα for IL-4 over related cytokines like IL-13 is mediated by key structural features, including recognition of helices A and D on IL-4.^[37] A critical mixed-charge pair in IL-4—glutamic acid at position 9 (Glu9) and arginine at position 88 (Arg88)—forms salt bridges with complementary residues on IL-4Rα (e.g., Arg in the receptor's D1 domain), contributing dominantly to the high-affinity interaction.^[43] In contrast, IL-13 possesses glutamine (Gln) at the equivalent position to Glu9, which lacks the negative charge and results in markedly lower affinity for IL-4Rα alone, ensuring ligand discrimination.^[43] This charged residue difference, along with surrounding hydrophobic and polar contacts, underpins the receptor's selective binding.^[44] The kinetics of IL-4 binding to IL-4Rα involve a rapid association rate constant (k_on) of approximately 1.3 × 10^7 M^{-1} s^{-1}, driven by electrostatic steering from positively charged residues on IL-4's helix C.^[45] The dissociation rate (k_off) is relatively slow at about 2.1 × 10^{-3} s^{-1} for the binary complex, yielding the observed K_d; however, in the type I receptor, γc engagement further slows dissociation through avidity effects, prolonging ligand occupancy.^[45] These rates were determined using surface plasmon resonance with immobilized IL-4Rα ectodomain.^[45] Soluble IL-4Rα (sIL-4Rα), generated by alternative splicing or proteolytic shedding, binds IL-4 with affinity comparable to the membrane-bound form (K_d ~150–300 pM), acting as a decoy receptor that neutralizes a substantial portion of circulating IL-4 and limits its bioavailability.^[46] This sequestration prevents excessive signaling without affecting IL-13 pathways under certain conditions.^[46] Site-directed mutagenesis studies from the 1990s identified critical residues for binding, such as Arg88 in IL-4, where substitution (e.g., R88Q or R88A) increases k_off by 70–300-fold and abolishes high-affinity interaction, confirming its role in the charged pair with Glu9.^[43] These experiments, combined with NMR spectroscopy, mapped the receptor-binding epitope and validated the structural basis of affinity.^[47]

Dimerization and Conformational Changes

Upon binding of interleukin-4 (IL-4) to the interleukin-4 receptor alpha chain (IL-4Rα), the receptor undergoes a conformational rearrangement that facilitates recruitment of a second receptor subunit, either the common gamma chain (γc) for type I receptors or IL-13 receptor alpha 1 (IL-13Rα1) for type II receptors, forming a ternary 1:1:1 complex.^[48] This process begins with high-affinity binding of IL-4 to the cytokine-binding domain of IL-4Rα (K_d ≈ 150 pM), which induces rotation of the D1 domain by approximately 45° relative to the fibronectin type III domains, aligning the structure for subsequent subunit engagement.^[3] In the assembled complex, the receptor chains are positioned with a separation of roughly 20 Å between their membrane-proximal regions, stabilizing the interface through a combination of hydrophobic and polar interactions across three residue clusters.^[3] The conformational dynamics triggered by ligand binding propagate structural changes from the extracellular to the intracellular domains, bringing the cytoplasmic tails of IL-4Rα and the second subunit into close proximity (on the order of 10 nm), which positions associated Janus kinases for cross-phosphorylation.^[29] Flexible hinge regions in the extracellular fibronectin type III domains allow pivoting and flexing, enabling signal propagation across the membrane while maintaining complex stability.^[48] These dynamics occur rapidly, with allosteric changes detectable via fluorescence resonance energy transfer (FRET) and nuclear magnetic resonance (NMR) spectroscopy propagating within microseconds, reflecting solvent-mediated adjustments at the protein interfaces.^[49] Type I and type II receptors exhibit distinct assembly kinetics: the type I complex (IL-4/IL-4Rα/γc) forms a stable ternary structure more slowly due to lower-affinity interactions (K_{d,2D} ≈ 1000 receptors/μm²), often requiring endosomal confinement for efficiency, whereas type II complexes (IL-4/IL-4Rα/IL-13Rα1 or IL-13/IL-13Rα1/IL-4Rα) assemble faster on the millisecond timescale with higher avidity (K_{d,2D} ≈ 180–480 receptors/μm²), permitting sequential ligand binding in the case of IL-13.^[29] This difference arises from the unique site III interaction in type II receptors involving the D1 domain of IL-13Rα1, which enhances interface stability compared to the canonical geometry of type I.^[48] Inhibitory mechanisms, such as those employed by monoclonal antibodies, target this dimerization: dupilumab binds with high affinity (K_d ≈ 33 pM) to a site on IL-4Rα that overlaps the IL-4 contact region, sterically hindering recruitment of γc or IL-13Rα1 and preventing complex formation.^[50]

Signal Transduction Pathways

JAK-STAT Signaling

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway represents the canonical signaling mechanism initiated by the interleukin-4 receptor (IL-4R) upon ligand binding. In the type I IL-4R complex, composed of the IL-4Rα subunit and the common gamma chain (γc), JAK1 constitutively associates with the intracellular domain of IL-4Rα, while JAK3 binds to γc. For the type II IL-4R complex, involving IL-4Rα and IL-13Rα1, JAK1 pairs with TYK2 (or JAK2 in certain cell types) on IL-13Rα1. Receptor dimerization, triggered by IL-4 binding to IL-4Rα, brings the associated JAKs into proximity, enabling their trans-phosphorylation and activation.^[2]^[51]^[52] Activated JAKs subsequently phosphorylate specific tyrosine residues on the IL-4Rα cytoplasmic tail, such as Y575, Y603, and Y631, creating docking sites for the SH2 domain of STAT6. Recruited STAT6 is then phosphorylated by the JAKs, primarily at Tyr641, leading to its homodimerization via reciprocal SH2-pTyr interactions. The phosphorylated STAT6 homodimer translocates to the nucleus, where it binds to gamma-activated sites (GAS) in target gene promoters. This cascade can be simplified as:

\text{IL-4 + IL-4R} \rightarrow \text{JAK1/JAK3 (or TYK2)-P} \rightarrow \text{STAT6-P (Tyr641)} \rightarrow \text{Nuclear translocation}

The pathway's activation was first linked to IL-4 in seminal studies identifying STAT6 as the key mediator.^[2]^[51]^[53] IL-4R signaling exhibits high specificity for STAT6 activation, distinguishing it from other cytokine receptors that preferentially engage STAT5 or STAT3; this selectivity arises from the precise tyrosine motifs on IL-4Rα that favor STAT6 recruitment over other STAT family members. Co-activation with transcription factors like GATA3 further amplifies STAT6-dependent gene expression in Th2 cells. Negative regulation occurs through suppressors of cytokine signaling (SOCS1 and SOCS3), which bind phosphorylated JAKs to inhibit their kinase activity, and protein inhibitors of activated STATs (PIAS3), which prevent STAT6 DNA binding by promoting its sumoylation.^[2]^[52] Mutations in STAT6 can disrupt IL-4R signaling; for instance, germline heterozygous gain-of-function variants, such as p.E382Q, enhance STAT6 phosphorylation and IL-4 responsiveness, leading to severe allergic dysregulation resembling aspects of hyper-IgE syndrome phenotypes with elevated IgE and Th2 bias. Conversely, partial loss-of-function variants reduce STAT6 activity and dampen IL-4 responses, though complete loss-of-function mutations in humans are rare and primarily studied in models showing impaired Th2 differentiation.^[54]

IRS and PI3K Pathways

Upon binding of interleukin-4 (IL-4) to its receptor, Janus kinase (JAK) family members phosphorylate tyrosine residues in the cytoplasmic domain of the IL-4 receptor α (IL-4Rα) chain, creating docking sites for insulin receptor substrate (IRS) adapter proteins.90356-5) The IL-4Rα contains a specific insulin/IL-4 receptor (I4R) motif, characterized by the sequence surrounding tyrosine 497 (Y497), which is essential for IRS recruitment; mutation of Y497 to phenylalanine abolishes IRS binding and downstream signaling.90356-5) This I4R motif, identified in 1990s studies as unique to IL-4R among cytokine receptors, is a serine/threonine-rich region that preferentially associates with IRS-1 and IRS-2 via their phosphotyrosine-binding (PTB) domains following JAK-mediated phosphorylation.^[55]^[56] Subsequent tyrosine phosphorylation of IRS-1/2 by JAKs generates multiple docking sites for the p85 regulatory subunit of phosphoinositide 3-kinase (PI3K), activating the enzyme.^[11] The IRS-PI3K complex catalyzes the production of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) from PIP2 at the plasma membrane.^[11] PIP3 recruits and activates 3-phosphoinositide-dependent kinase 1 (PDK1) and protein kinase B (Akt), leading to Akt phosphorylation and activation of downstream targets such as mammalian target of rapamycin (mTOR) while inhibiting Forkhead box O (FoxO) transcription factors.^[57] This pathway promotes cell survival through upregulation of anti-apoptotic proteins like Bcl-xL and enhances metabolic responses, including glucose uptake via translocation of glucose transporter 4 (GLUT4) to the cell surface.^[51] In macrophages and B cells, IRS-2-mediated PI3K signaling drives expression of genes associated with alternative activation, such as arginase 1 and Ym1.^[11] The IRS-PI3K pathway is more prominent in type I IL-4 receptors (IL-4Rα/γc), which robustly phosphorylate IRS-2, compared to type II receptors (IL-4Rα/IL-13Rα1), where activation is weaker even with equivalent STAT6 engagement.^[11] In B cells, the IRS pathway cooperates with JAK-STAT signaling to amplify IL-4-induced proliferation and differentiation, regulating cell cycle inhibitors like p27Kip1, though the pathways operate independently in terms of initial activation.^[58] IRS-2 knockout mice exhibit impaired IL-4-dependent metabolic signaling and macrophage polarization but retain intact STAT6-mediated immune responses, highlighting the pathway's specialized role.^[59] Regulation occurs through negative feedback mechanisms, including suppressor of cytokine signaling 1 (SOCS1), which associates with IRS-2 post-stimulation, promotes its ubiquitination, and targets it for proteasomal degradation, thereby limiting tyrosine phosphorylation duration and preventing prolonged signaling.^[60] Additionally, phosphatase and tensin homolog (PTEN) counteracts PI3K by dephosphorylating PIP3 to PIP2, terminating the signal; IL-4 stimulation can attenuate PTEN activity via interactions that reduce its phosphatase function.00492-8)

Biological Roles

Immune System Regulation

The interleukin-4 receptor (IL-4R), particularly through its alpha chain (IL-4Rα), plays a pivotal role in adaptive immunity by promoting the differentiation of naive CD4+ T cells into Th2 cells. Binding of IL-4 to IL-4R activates the JAK-STAT pathway, with STAT6 serving as a key mediator that induces the expression of transcription factors such as GATA3 and c-Maf. These factors drive the production of Th2 cytokines including IL-4, IL-5, and IL-13, thereby establishing a feedback loop that reinforces Th2 polarization and maintains the balance against Th1 responses. In B cells, IL-4R signaling is essential for humoral immunity, specifically facilitating class-switch recombination to IgE, which is critical for anti-parasitic defenses and allergic responses. IL-4 induces germline transcription of the epsilon heavy chain via STAT6-dependent mechanisms, enabling B cells to produce IgE antibodies. Additionally, IL-4R engagement upregulates CD23 (FcεRII), the low-affinity IgE receptor, enhancing antigen presentation and B cell activation. In murine models, this pathway also inhibits the production of IgG2a, a Th1-associated isotype, thereby skewing the antibody response toward Th2 dominance.^[61]^[62] IL-4R contributes to innate immunity by modulating key effector cells. The Type I IL-4R (IL-4Rα/γc) on mast cells promotes their development and enhances degranulation in response to allergens or parasites, amplifying immediate hypersensitivity reactions. In contrast, the Type II IL-4R (IL-4Rα/IL-13Rα1), expressed on eosinophils, supports their survival and recruitment to inflammatory sites through IL-4 and IL-13 signaling. Furthermore, IL-4R drives alternative activation of macrophages to an M2 phenotype, characterized by anti-inflammatory and tissue-repair functions, which aids in resolving infections while limiting excessive inflammation.^[63] Through these mechanisms, IL-4R modulates inflammatory and anti-viral responses by constraining overzealous Th1-mediated immunity, particularly during helminth infections where Th2 dominance facilitates parasite clearance. This regulatory function helps prevent tissue damage from unchecked pro-inflammatory cytokines like IFN-γ.^[64] Studies in IL-4R knockout mice demonstrate the receptor's indispensability for Th2 responses; these animals exhibit defective Th2 differentiation, resulting in impaired expulsion of helminth parasites such as Nippostrongylus brasiliensis due to reduced IL-13 production and impaired goblet cell hyperplasia, alongside diminished allergic manifestations.^[65] Evolutionarily, IL-4R signaling is conserved across jawed vertebrates, emerging alongside adaptive immunity to bolster defenses against parasitic infections, with IL-4Rα orthologs identified in species from fish to mammals.^[66]^[64]

Non-Immune Functions

The interleukin-4 receptor (IL-4R), particularly its type II isoform (IL-4Rα/IL-13Rα1), is expressed on fibroblasts in non-immune tissues, where it mediates IL-4 and IL-13 signaling to promote fibrosis and wound healing processes. Activation of type II IL-4R on these cells induces collagen synthesis through STAT6-dependent pathways, contributing to extracellular matrix deposition and tissue remodeling during repair.^[67] Additionally, IL-4R signaling involves Akt activation, which further supports fibroblast proliferation and survival in fibrotic environments, as seen in models of organ fibrosis.^[68] This receptor-mediated response is implicated in pathological tissue stiffening, such as in pulmonary or hepatic fibrosis, where sustained signaling exacerbates remodeling beyond normal healing.^[69] In neural tissues, IL-4R expression on microglia facilitates M2-like polarization, which aids in resolving neuroinflammation and providing neuroprotection. IL-4 binding to IL-4R promotes this anti-inflammatory shift, enhancing phagocytosis of debris and reducing pro-inflammatory cytokine release, thereby mitigating neuronal damage in injury models.^[70] In Alzheimer's disease contexts, IL-4R signaling on microglia supports neuroprotective effects, as demonstrated by improved cognitive performance in transgenic mouse models following IL-4 administration, which correlates with decreased amyloid pathology and enhanced M2 markers.^[71] This role extends to broader brain repair mechanisms, where IL-4R influences microglial metabolism and phenotype to favor tissue resolution over chronic inflammation.^[72] IL-4R contributes to metabolic regulation in adipose tissue via the IRS pathway, which enhances insulin sensitivity in adipocytes. Type I IL-4R (IL-4Rα/γc) activation recruits IRS-2, leading to PI3K/Akt signaling that improves glucose uptake and reduces lipid accumulation, counteracting insulin resistance in obesity models.^[11] Genetic variants in IL4RA are associated with increased obesity risk, particularly severe forms, as they alter receptor function and inflammatory responses in adipose tissue, promoting metabolic dysregulation.^[73] Non-hematopoietic IL-4Rα expression specifically drives adipose lipolysis and insulin sensitivity, highlighting its role in energy homeostasis independent of immune cells.^[74] Through cross-signaling with IL-13 via type II IL-4R, the receptor influences epithelial barrier integrity in gut and lung tissues, though effects often involve modulation of tight junctions leading to altered permeability. In airway epithelia, IL-4/IL-13 binding to IL-4R disrupts zonula occludens-1 localization, increasing paracellular leakage and contributing to barrier compromise in inflammatory states.^[75] Similar signaling in intestinal epithelia affects claudin expression, potentially exacerbating permeability during homeostasis challenges, with implications for mucosal defense.^[76] In cancer contexts, IL-4R on tumor cells promotes survival signaling via STAT6 and PI3K pathways, enhancing proliferation and resistance to apoptosis in various solid tumors. Paradoxically, IL-4R activation on tumor-associated macrophages (TAMs) drives M2 polarization, contributing to the pro-tumor microenvironment through immunosuppression and tissue remodeling.^[77] This dual role underscores IL-4R's context-dependent influence in the tumor microenvironment.^[78] During embryogenesis, IL-4R supports lung branching morphogenesis by regulating epithelial-mesenchymal interactions essential for airway development. Expression of IL4RA increases with gestational age, correlating with progressive lung bud formation and patterning in human fetal tissues.^[79]

Clinical Significance

Role in Diseases

Dysregulation of the interleukin-4 receptor (IL-4R) plays a central role in allergic diseases, where overactive signaling promotes Th2-dominated inflammation, elevated IgE production, and eosinophil recruitment in conditions such as asthma and atopic dermatitis.^[80] The I50V polymorphism in the IL4R gene is associated with increased susceptibility to asthma, with meta-analyses indicating a modest risk elevation (odds ratio approximately 1.13 in dominant models), particularly through enhanced Th2 cell activity and higher total IgE levels.^[81] Similarly, the Q576R variant correlates with greater severity of atopic dermatitis by amplifying allergic skin inflammation and cytokine responses.^[82] In autoimmune disorders, hyperactive IL-4R signaling contributes to fibrosis in systemic sclerosis, where elevated IL-4 and IL-13 levels in patient serum drive Th2 polarization in fibrotic tissues, promoting collagen deposition and extracellular matrix remodeling.^[83] Conversely, IL-4R activation appears protective in Th1-driven diseases like psoriasis, as IL-4 induces Th2 differentiation that suppresses pro-inflammatory Th1 responses.^[84] Impaired IL-4R function, often linked to STAT6 defects, heightens susceptibility to severe infections such as chronic mucocutaneous candidiasis by disrupting balanced Th2 responses needed for mucosal immunity.^[85] In HIV infection, exaggerated IL-4R signaling exacerbates disease progression through B cell dysregulation, leading to polyclonal B cell activation, impaired antibody responses, and increased viral propagation via enhanced syncytia-inducing HIV-1 isolates.^[86]^[87] In cancer, IL-4R expression on tumor cells, particularly in breast cancer, fosters metastatic potential by activating STAT6-mediated survival and proliferation pathways, enabling colonization at distant sites.^[88] Beyond immune-related pathologies, IL4R is implicated in the inflammatory drivers of severe obesity, with roles in insulin signaling pathways.^[89]

Therapeutic Applications

Dupilumab, a monoclonal antibody targeting the IL-4 receptor alpha subunit (IL-4Rα), inhibits signaling through both type I and type II IL-4 receptors, thereby blocking the actions of IL-4 and IL-13. It was approved by the FDA in 2017 for moderate-to-severe atopic dermatitis and uncontrolled asthma in adults and children. Phase III trials, such as LIBERTY ASTHMA QUEST, demonstrated up to 60% reduction in severe exacerbations and improved lung function in patients with type 2 asthma.^[90]^[91] Other biologics targeting the IL-4/IL-13 pathway include lebrikizumab, a monoclonal antibody against IL-13 that indirectly modulates type II IL-4 receptor signaling by preventing IL-13 binding to IL-4Rα/IL-13Rα1 complexes. Approved in 2023 for moderate-to-severe atopic dermatitis, lebrikizumab has shown efficacy in reducing skin lesions and pruritus in phase III trials. In contrast, pascolizumab, an anti-IL-4 monoclonal antibody, failed to demonstrate significant clinical benefit in phase II trials for asthma, leading to its discontinuation due to limited efficacy despite good tolerability.^[92]^[93] Small molecule inhibitors, such as Janus kinase (JAK) inhibitors, indirectly target IL-4R signaling by blocking downstream JAK-STAT pathways activated upon receptor ligation. Upadacitinib, a selective JAK1 inhibitor, is approved for moderate-to-severe atopic dermatitis and has shown significant improvements in skin clearance and itch reduction in phase III trials for atopic diseases. Ongoing trials explore its use in other IL-4R-driven conditions like asthma.^[94] Emerging gene therapy approaches include CRISPR-Cas9 editing of IL4R gene polymorphisms associated with heightened allergic responses, with preclinical studies demonstrating potential to reduce IL-4 signaling in allergy models. In cancer, early preclinical research targets IL4R to mitigate IL-4-induced exhaustion of chimeric antigen receptor T (CART) cells, enhancing antitumor efficacy.^[95]^[96] Therapeutic targeting of IL-4R carries challenges, including immunosuppression-related side effects such as increased risk of infections, particularly upper respiratory tract infections observed in clinical trials of dupilumab and similar agents. Patient selection is aided by biomarkers like serum periostin, which indicates type 2 inflammation and predicts response to IL-4R/IL-13 inhibitors, enabling more precise therapy in atopic diseases.^[97] In August 2025, a biosimilar of dupilumab received approval for clinical trials in China.^[98] Novel oral modulators of IL-4R signaling are in phase II trials for fibrotic diseases, building on preclinical evidence of their antifibrotic effects via pathway inhibition. Applications beyond allergy, such as in inflammatory bowel disease (IBD), remain exploratory, with preclinical data suggesting potential in modulating Th2-driven inflammation in ulcerative colitis.^[99]

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IL-4 and IL-13 are known as T-helper type 2 (Th2) cytokines (6) because they are produced by Th2 cells in response to antigen-receptor engagement. They are also ...Fig. 2 · Fig. 3 · Fig. 4
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3566 - Gene ResultIL4R interleukin 4 receptor [ (human)] - NCBI
Sep 9, 2025 · IL-4R is expressed on alpha and beta cells of human pancreata. The role of interleukin 4 and IL-4RA in intervertebral disc degeneration: ...
[10]
Common variations in the IL4R gene affect splicing and influence ...
Common variations in the IL4R gene affect splicing and influence natural expression of the soluble isoform ... alternative splicing selection of IL4R in vivo.
[11]
In Situ Identification of Both IL-4 and IL-10 Cytokine–Receptor ...
The IL-4R is ubiquitously expressed and has been detected at the surface of B cells, T cells, mast cells, eosinophils, basophils, monocytes, macrophages, and ...<|separator|>
[12]
IL-4 receptor mutations - ScienceDirect.com
Receptors for IL-4 are expressed on hematopoietic cells and a range of nonhematopoietic cells including epithelial, endothelial, muscle, fibroblast and liver ...
[13]
The Regulatory Effects of Interleukin-4 Receptor Signaling on ...
Interleukin-4 (IL-4) receptor (IL-4R) signaling plays a pivotal role in type 2 immune responses. Type 2 immunity ensures several host-protective processes ...
[14]
Role of interleukin-4 in regulation of age-related inflammatory ...
We report that functional IL-4 receptors are expressed on granule cells of the dentate gyrus and that receptor activation results in phosphorylation of JAK1 and ...Missing: IL4R | Show results with:IL4R
[15]
Transcriptional regulation by STAT6 - PMC - PubMed Central - NIH
STAT6, activated by IL-4 and IL-13, regulates transcription, acting as both a positive and negative regulator, and is critical for the immune system.Missing: IL4RA miRNAs
[16]
IL-4 receptor expression on CD8 + T cells is required for the ...
These results demonstrate that IL-4/IL-4R interactions on CD8+ T cells play a critical role in modulating the development and tissue distribution of memory ...
[17]
The IL-4/STAT6 signaling axis establishes a conserved microRNA ...
Our findings identify a conserved IL-4/STAT6-regulated microRNA signature in alternatively activated human and mouse macrophages. Moreover, our study indicates ...Missing: IL4RA | Show results with:IL4RA
[18]
Interleukin-4 Receptor Alpha: From Innate to Adaptive Immunity in ...
In addition to cell-surface localization, soluble forms of both IL-4Rα and IL-13Rα2 exist (Figure 1), which are capable of binding IL-4 and IL-13 with high ...
[19]
Th2 cytokines and asthma — Interleukin-4: its role in the ...
Feb 19, 2001 · Soluble recombinant human IL-4 receptor (rhuIL-4R; Nuvance™; Immunex) is the extracellular portion of human IL-4Rα, the gene encoding which has ...
[20]
IL-4-ever young: Type 2 cytokine signaling in macrophages slows ...
Mar 12, 2024 · Macrophages activated via the IL-4 receptor possess non-immune functions that support tissue homeostasis, but their specific role in aging ...
[21]
A polymorphism in the interleukin-4 receptor affects the ability of ...
A single-nucleotide polymorphism (SNP), I50V, in the coding region of the human IL-4 receptor (IL-4R) is associated with rapid development of erosive disease in ...
[22]
[PDF] IL4RAgene expression in relation to I50V, Q551R and C-3223T ...
Jan 30, 2021 · A number of studies have proven the association between IL4RA gene polymorphisms and asthma and atopy, but it is still an open question whether ...
[23]
COMMENTARY: IL-4 AND IL-13 RECEPTORS AND SIGNALING
Signaling through the type I receptor leads to activation JAKs and downstream signaling adaptor molecules STAT6 and IRS-2, whereas signaling through the type II ...
[24]
p24394 · il4ra_human - UniProt
The functional IL4 receptor is formed by initial binding of IL4 to IL4R. Subsequent recruitment to the complex of the common gamma chain, in immune cells, ...Missing: exons weight
[25]
Recombinant Human IL-4R alpha Protein 230-4R-025 - R&D Systems
$$45 deliveryInterleukin 4 Receptor alpha (IL-4 R alpha ), also known as CD124 and BSF receptor, is a widely expressed 140 kDa transmembrane glycoprotein in the class I ...
[26]
Interleukin-4 Receptor - an overview | ScienceDirect Topics
The extracellular segment of IL-4Rα consists of two type III fibronectin domains. ... fibronectin type III (FNIII) like domain. These constitutive elements ...
[27]
Dynamics and Interaction of Interleukin-4 Receptor Subunits in ... - NIH
IL-4Rα cytoplasmic deletion constructs (IL-4Ram266 constructs comprised of the amino acids 1–266) lacking the STAT6 docking site dominantly suppressed the ...Missing: weight | Show results with:weight
[28]
Common Gamma Chain - an overview | ScienceDirect Topics
The common gamma chain is a glycoprotein shared by receptors for interleukins like IL-2, IL-4, IL-7, IL-9, and IL-15, and is about 64 kDa.Missing: weight | Show results with:weight<|separator|>
[29]
The common γ-chain cytokine receptor: tricks-and-treats for T cells
The γc cytokine receptor is the shared receptor subunit for the cytokines IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, which are collectively referred to as γc ...
[30]
Characterization of the membrane-bound and a soluble form of ...
Here we present the genomic structure and organization of huIL-4Rα. The promotor region shows binding sites for several transcription factors involved in ...Missing: weight glycoprotein
[31]
Entry - *147781 - INTERLEUKIN 4 RECEPTOR; IL4R - OMIM
Interleukin-4 (IL4; 147780) is a cytokine produced by T cells that plays a major role in immunoglobulin E (IgE) production and that regulates proliferation ...Missing: kb | Show results with:kb
[32]
Evolution of Class I cytokine receptors
Jul 18, 2007 · Although individual Class I helical cytokine receptor chains vary in overall topology, they all posses a conserved 200 amino acid extracellular ...Identification Of Zebrafish... · Discussion · Functional Considerations
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https://academic.oup.com/intimm/article/11/12/1965/837660
[34]
THE IL-4 RECEPTOR: Signaling Mechanisms and Biologic Functions
The murine IL-4Rα is 785 amino acids long with a 553 amino acid cy- ... In particular, mutation of P488 to A in the full-length human IL-4Rα greatly diminished ...
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https://bmcecolevol.biomedcentral.com/articles/10.1186/1471-2148-7-120
[36]
Recombinant Mouse IL-4R alpha Fc Chimera Protein, CF 530-MR-100
Mature mouse IL-4 R alpha consists of a 208 amino acid ... Within the ECD, mouse IL-4 R alpha shares 51% and 76% aa sequence identity with human and rat IL-4 R ...
[37]
Interleukin-4 receptor signaling and its binding mechanism
Here in this review, we discuss the structural details of IL-4 and IL-4Rα subunit and the structural similarities between IL-4 and IL-13.
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Tuning the Cytokine Responses: An Update on Interleukin (IL)-4 and ...
Upon IL-4 binding to IL-4Rα, the IL-4/IL-4Rα-complex will bind a secondary receptor chain, either IL-2Rγc (γc) or IL-13Rα1 (Figure 1). The expression of these ...Missing: directed mutagenesis
[39]
A mixed-charge pair in human interleukin 4 dominates high-affinity interaction with the receptor α chain | PNAS
### Summary of Charged Residues and Affinity in IL-4 vs IL-13
[40]
Molecular and structural basis of cytokine receptor pleiotropy ... - NIH
Here we present the crystal structures of the complete set of Type I (IL-4Rα/γ c /IL-4) and Type II (IL-4Rα/IL-13Rα1/IL-4, IL-4Rα/IL-13Rα1/IL-13
[41]
A mixed-charge pair in human interleukin 4 dominates high-affinity ...
Human interleukin 4 (IL-4) binds to its cellular receptor with a Kd in the subnanomolar range, similar to many other 4-helix-bundle proteins interacting ...
[42]
IL-4 receptor alpha is an important modulator of IL-4 and ... - PubMed
We found that IL-4 bound to the extracellular domain of IL-4Ralpha (soluble human (sh)IL-4Ralpha) with high affinity and specificity. In contrast with the ...
[43]
https://www.pnas.org/doi/10.1073/pnas.94.5.1657
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Aspects of receptor binding and signalling of interleukin-4 ... - PubMed
Aspects of receptor binding and signalling of interleukin-4 investigated by site-directed mutagenesis and NMR spectroscopy. J Mol Biol. 1994 Apr 8;237(4):423-36 ...Missing: Arg88 1990s
[45]
Molecular and Structural Basis of Cytokine Receptor Pleiotropy in ...
Jan 25, 2008 · Here we present the crystal structures of the complete set of type I (IL-4Rα/γ c /IL-4) and type II (IL-4Rα/IL-13Rα1/IL-4, IL-4Rα/IL-13Rα1/IL-13
[46]
Insights into receptor structure and dynamics at the surface of living ...
Mar 22, 2023 · The protein construct IL-4Rα* is composed of an exposed N-terminal hexahistidine stretch (His-tag), a truncated, signaling-deficient version of ...
[47]
Biological Therapy of Severe Asthma with Dupilumab, a Dual ... - MDPI
Jun 19, 2022 · Dupilumab is a dual receptor antagonist which occupies and blocks IL-4Rα, thus preventing its dimerization with the other components of type ...
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Interleukin-4 (IL-4) Pathway | Science's STKE
IL-4 can stimulate two receptor complexes, type I and type II (12). ... The dimerization activates the Janus kinases (Jaks) associated with the cytoplasmic tails ...<|control11|><|separator|>
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https://www.nature.com/articles/s41467-023-37284-4
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https://www.mdpi.com/2076-393X/10/6/974
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A partial loss-of-function variant in STAT6 protects against type 2 ...
Oct 16, 2024 · Here, we report a rare partial loss-of-function (LOF) missense variant in STAT6 that reduces T2 inflammatory responses and is protective against ...
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https://doi.org/10.1146/annurev.immunol.17.1.701
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Targeted Inactivation of the IL-4 Receptor α Chain I4R Motif ...
The insulin/interleukin-4 (IL-4) receptor (I4R) motif mediates the association of insulin receptor substrate (IRS)-2 with the interleukin-4 (IL-4)Rα chain.
[54]
IL-4 and IL-13 Receptor Signaling From 4PS to Insulin ... - Frontiers
A functional IL-4 receptor is composed of two transmembrane proteins. The IL-4Rα chain binds IL-4 with high affinity, leading to dimerization with the common ...
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Stat6 and IRS-2 Cooperate in Interleukin 4 (IL-4) - PubMed Central
Stat6 and IRS-2 are two important signaling proteins that associate with the cytoplasmic tail of the interleukin 4 (IL-4) receptor.Missing: talk fibroblasts
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Gene ResultIrs2 insulin receptor substrate 2 [ (house mouse)] - NCBI
Sep 24, 2025 · IRS-2-dependent IL-4 signaling in macrophages is impaired in models ... in insulin receptor substrate-2 (IRS-2) knockout mice ...
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https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.01037/full
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STAT6 is required for IL-4-induced germline Ig gene ... - PubMed - NIH
Transcription of the germline C gamma1 and C epsilon Ig genes is believed to be a necessary prerequisite for isotype switching to IgG1 and IgE, respectively ...
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Interleukin 4 causes isotype switching to IgE in T cell-stimulated ...
These experiments definitively prove that IL-4 causes specific heavy chain class switching to IgE in Th2-stimulated B cell cultures.Missing: 4R | Show results with:4R
[60]
An Update on Interleukin (IL)-4 and IL-13 Receptor Complexes
Jun 7, 2018 · ... IL-4 drives the immunoglobulin (Ig) class switch to IgG1 and IgE, and in macrophages, IL-4 and IL-13 induce alternative macrophage activation.<|separator|>
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Evolution and function of interleukin-4 receptor signaling in adaptive ...
Mar 6, 2020 · Here, we review when IL-4R signaling cytokines appeared during evolution relative to neutrophils and adaptive immunity.
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Concerted IL-25R and IL-4Rα signaling drive innate type 2 effector ...
Sep 21, 2018 · Immune expulsion of helminth parasites is driven by two key pathways mediated by soluble cytokines ligating to the IL-4 and IL-25 receptors ...
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Interleukins and Interleukin Receptors Evolutionary ... - PubMed
May 26, 2021 · CD4+ T cells have emerged during the divergence of jawed vertebrates. However, little is known about the evolution of interleukins and their ...
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Interleukin-4 induces the activation and collagen production of ...
Interleukin-4 induces the activation and collagen production of cultured human intrahepatic fibroblasts via the STAT-6 pathway. Lab Invest. 2008 Sep;88(9): ...Missing: Akt | Show results with:Akt
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Increased levels of Gab1 and Gab2 adaptor proteins skew ...
Our results further demonstrated that Gab1 regulates AKT activation, whereas Gab2 mediates STAT6 enhancement in response to IL-4, which supports the notion that ...
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The IL-4/IL-13 signaling axis promotes prostatic fibrosis | PLOS One
Oct 6, 2022 · These finding suggest that the IL-4/IL-13 signaling axis is a powerful, but therapeutically targetable, pro-fibrotic mechanism in the lower urinary tract.Missing: synthesis | Show results with:synthesis
[67]
Interleukin-4 Is Essential for Microglia/Macrophage M2 Polarization ...
Jan 5, 2016 · The cytokine IL-4 improves long-term neurological outcomes after stroke, perhaps through M2 phenotype induction in microglia/macrophages.
[68]
Evaluating the Effect of Interleukin-4 in the 3xTg Mouse Model of ...
May 13, 2020 · Our findings indicate that a single intracranial IL-4 injection positively modulated performance of 3xTg AD mice in a Novel Object Recognition task.
[69]
IL-4 in the brain: a cytokine to remember. - Abstract - Europe PMC
IL-4 then may skew meningeal macrophages to M2, which have been shown to reverse cognitive defects of immunosuppresed mice. IL-4 additionally affects astrocytes ...Interleukin-4: A Cytokine To... · Il-4 Signaling · Il-4 In Neurological...<|separator|>
[70]
Multiomics reveal key inflammatory drivers of severe obesity - Olink
Our integrative approach identified inflammatory genes, including IL4R, ZNF438, and LILRA5. Several genes displayed transcriptomic effects on severe obesity in ...
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Non-hematopoietic IL-4Rα expression contributes to fructose-driven ...
Jul 23, 2021 · Interleukin-4 (IL-4) and IL-13 signaling via IL-4Rα regulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis in obesity.
[72]
IL-4 and IL-13 Compromise the Sinonasal Epithelial Barrier ... - NIH
Sinonasal epithelial exposure to Th2 cytokines IL-4 and IL-13 results in alterations in intercellular junction proteins, reflecting increased epithelial ...Th2 Cytokine Exposure · Immunofluorescence Labeling... · Tight Junction And Adherens...
[73]
Interleukins 4 and 13 Increase Intestinal Epithelial Permeability by a ...
We examined the signal transduction events in- volved in IL-4 and IL-13 regulation of epithelial paracel- lular permeability using T84 cells, a model human co-.<|separator|>
[74]
IL4 Receptor–Targeted Proapoptotic Peptide Blocks Tumor Growth ...
Given that IL4R expression is upregulated in both tumor cells and M2-type TAMs, we aimed to inhibit tumors by targeted killing of IL4R-expressing cells. For ...Flow Cytometry Analysis Of... · Results · Il4r Expression Is Closely...
[75]
Alternative activation of tumor-associated macrophages by IL-4
Treatment with IL-4 results in a significant increase in cathepsin activity, along with upregulation of several 'M2' marker genes including Ccl17, Ccl22, Arg1, ...Effects Of Il-4 On... · Il-4-Associated Gene... · Il-4-Associated Tam...
[76]
Expression analysis of asthma candidate genes during human and ...
Expression of NOD1, EDN1 and IL4R were positively correlated with gestational age in the human data, whereas ROBO1 and PLAUR were negatively correlated (i.e. ...
[77]
IL-4-induced SOX9 confers lineage plasticity to aged adult lung stem ...
Jul 31, 2024 · We show that IL4Ra signaling in macrophages promotes regeneration of the alveolar epithelium after bleomycin-induced lung injury.
[78]
Association of Interleukin-4 Receptor α Chain I50V Gene Variant ...
Asthma patients have a higher prevalence of the I allele, reflecting the significance of Th2 cells. Although total IgE and IL-17A levels increased in both ...
[79]
Association between Interleukin-4 Receptor alpha Chain (IL4RA ...
There was a significant association between the IL4RA I50V polymorphism and asthma risk in a dominant genetic model (OR = 1.13, 95% CI 1.04-1.23, P = 0.005).
[80]
The IL-4Rα Q576R polymorphism is associated with increased ...
Mice with the IL-4Rα Q576R mutation demonstrate exaggerated allergic skin inflammation in response to epicutaneous (EC) sensitization with OVA antigen.Missing: UniProt P24394 domains isoforms
[81]
Interleukin-4 and interleukin-13 as possible therapeutic targets in ...
Levels of IL-4, IL-13 and CXCL4 are higher in the serum of SSc patients compared to healthy controls. Fibrotic tissue in SSc displays a Th2 polarized CD4+ cell ...
[82]
Interleukin-4 therapy of psoriasis induces Th2 responses ... - PubMed
IL-4 therapy can induce Th2 differentiation in human CD4+ T cells and has promise as a potential treatment for psoriasis, a prototypic Th1-associated ...
[83]
Human germline gain-of-function in STAT6: from severe allergic ...
Germline heterozygous GOF STAT6 variants have been recently discovered to cause a broad and severe human clinical phenotype of asthma, atopic dermatitis, food ...
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Dual effect of interleukin 4 on HIV-1 expression: Implications for viral ...
We report that interleukin 4 (IL-4) inhibits the propagation of non-syncytia-inducing and increases the propagation of syncytia-inducing HIV-1 isolates by two ...
[85]
Cytokine production and dysregulation in HIV pathogenesis
These cytokines, particularly IL-4, result in B cell activation and antibody production. ... B cell antibody responses and HIV-specific CD8+ T cell effector ...
[86]
IL-4 receptor ILR4α regulates metastatic colonization by mammary ...
The IL4/IL4R interaction has been shown to enhance the proliferation and survival of breast cancer cells in vitro [6,7], and the survival of other epithelial ...Missing: sIL- 4Rα
[87]
Expression of IL4Rα and IL13Rα1 are associated with poor ... - NIH
In addition, elevated expression of IL4Rα and/or IL13Rα1 were associated with poor prognosis of glioblastoma [9], mesothelioma [10], breast cancer [11], renal ...
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Multiomics reveal key inflammatory drivers of severe obesity
Mar 4, 2025 · Common body mass index-associated variants confer risk of extreme obesity. Hum. Mol. Genet. 2009;18:3502–3507. doi: 10.1093/hmg/ddp292. [DOI] ...
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IL-4 shapes microglia-dependent pruning of the cerebellum during ...
Nov 1, 2023 · Here, we show that low levels of IL-4 in the early postnatal stage delineate a critical period in which microglia extensively prune cerebellar neurons.
[90]
Early‐life IL‐4 administration induces long‐term changes in ...
Dec 16, 2024 · Early postnatal allergic airway inflammation induces dystrophic microglia leading to excitatory postsynaptic surplus and autism‐like behavior.
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Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent ...
May 21, 2018 · Dupilumab treatment has been shown to reduce the rate of exacerbations and improve lung function in patients with uncontrolled moderate-to-severe asthma.
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Dupilumab - StatPearls - NCBI Bookshelf
Feb 28, 2024 · The US Food and Drug Administration (FDA) approved the medication in April 2017 to treat moderate-to-severe, resistant, atopic dermatitis ...
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Lebrikizumab: a new anti-IL-13 agent for treating moderate-to ...
Dec 6, 2024 · Lebrikizumab, a new humanized monoclonal antibody targeting IL-13, has been approved for treating moderate-to-severe AD.
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Targeting Interleukin-4 in Asthma: Lost in Translation? - ATS Journals
Feb 27, 2012 · However, a subsequent large-scale, multidose phase II trial in steroid-naive subjects with asthma was terminated because preliminary data showed ...
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JAK Inhibitors in the Treatment of Atopic Dermatitis - PMC
Topical and oral JAK inhibitors reversibly inhibit JAK proteins with varying specificity: abrocitinib and upadacitinib (JAK1); ruxolitinib and baricitinib (JAK1 ...
[96]
IL-4 drives exhaustion of CD8+ CART cells | Nature Communications
Sep 12, 2024 · The IL-4 mAb, pascolizumab, was well-tolerated in a phase II clinical trial for the treatment of asthma; dupilumab, a mAb blocking IL-4 and IL ...
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IL4R Gene Editing - Creative Biogene CRISPR/Cas9 Platform
CRISPR/Cas9 PlatformCB provides CRISPR/Cas9-mediated IL4R gene editing in cells or animals to support your research ... These pre-clinical studies showed that the ...
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Using Periostin as a Biomarker in the Treatment of Asthma - PMC
Periostin has 2 characteristics as a biomarker for early diagnosis of asthma: surrogate biomarkers for type 2 immunity and tissue remodeling.
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CSPC's Biosimilar Dupilumab PRC Clinical Trials Approved
Aug 19, 2025 · On 19 August 2025, CSPC Pharmaceutical announced that it has received approval from China's National Medical Products Administration (NMPA) ...
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Recent Advances in the Inhibition of the IL-4 Cytokine Pathway for ...
In more recent years, a phase II clinical trial with pascolizumab was conducted with asthmatic patients. While no issues were raised with the safety of the ...Missing: failure | Show results with:failure