Alternative titles; symbols
HGNC Approved Gene Symbol: IL4
Cytogenetic location: 5q31.1 Genomic coordinates (GRCh38): 5:132,673,989-132,682,678 (from NCBI)
The proliferation and differentiation of B cells is mediated in part by soluble factors produced by lectin- or antigen-activated T cells. In mice, at least 2 distinct B-cell growth factors have been described. One of these is called BSF1. Two laboratories isolated cDNA clones encoding a polypeptide with BSF1 activity from a cDNA library made with mRNA from conconavalin A-activated mouse helper T cells. Based on homology to mouse Bsf1 cDNA, Yokota et al. (1986) isolated the human equivalent from a cDNA library of conconavalin A-activated human T cells. The human cDNA contained a single open reading frame encoding a protein of 153 amino acids, including a putative signal peptide. The mouse and human genes and their protein products show structural and functional similarities. The lymphokine, which they termed IL4, also has T-cell and mast cell growth factor activities distinct from IL2 (147680) and IL3 (147740). IL4 is an 18-kD glycoprotein.
Arai et al. (1989) found that the IL4 gene has 4 exons and is approximately 10 kb in size.
By a combination of in situ hybridization to normal human chromosomes and Southern blot analysis of a series of mouse-human hybrid cell lines, Sutherland et al. (1988) mapped IL4 to 5q31, the same location as IL5 (147850) and other hemopoietic growth factor genes. Takahashi et al. (1989) mapped the mouse Il4 gene to chromosome 11 by observations of RFLPs in recombinant inbred mouse strains. Saltman et al. (1993) determined an order for 14 genes on 5q23-q33; IL4 was the most centromeric and ADRA1 (104219) the most distal in a span of approximately 15 Mb. By fluorescence in situ hybridization, Le Beau et al. (1993) mapped the gene to 5q31.1. Smirnov et al. (1995) showed that the IL13 gene (147683) is located 12 kb upstream from the IL4 gene in a tail-to-head orientation and discussed the similarities between the 2 genes in their organization.
Kotanides and Reich (1996) identified a specific STAT6 (601512) DNA-binding target site in the promoter of the IL4 receptor gene (IL4R; 147781) and showed that STAT6 activates IL4 gene expression via this site.
Dickensheets et al. (1999) presented evidence that interferons inhibit IL4-induced activation of STAT6 and STAT6-dependent gene expression, at least in part, by inducing expression of SOCS1 (603597).
Lewis et al. (1993) found bone disease that appeared to result from markedly decreased bone formation by osteoblasts, strikingly similar to the changes observed in cases of severe low-turnover human involutional osteoporosis, in transgenic mice that inappropriately expressed Il4 under the direction of the proximal promoter for the lymphocyte-specific protein tyrosine kinase gene (LCK; 153390). By 2 months of age, female and male lck/Il4 mice invariably developed severe osteoporosis of both cortical and trabecular bone. Osteoporosis is a common complication in patients with the hyper-IgE syndrome (147060), a heritable immunodeficiency in which B lymphocytes function as if exposed to excess IL4 (Leung and Geha, 1988).
Long-range regulatory elements are difficult to discover experimentally; however, they tend to be conserved among mammals, suggesting that cross-species sequence comparisons should identify them. To search for regulatory sequences, Loots et al. (2000) examined about 1 megabase of orthologous human and mouse sequences for conserved noncoding elements with greater than or equal to 70% identity over at least 100 basepairs. Ninety noncoding sequences meeting these criteria were discovered, and the analysis of 15 of these elements found that about 70% were conserved across mammals. Characterization of the largest element in transgenic mice propagating human 5q31 yeast artificial chromosomes revealed it to be a coordinate regulator of 3 genes, interleukin-4, interleukin-13, and interleukin-5. This conserved noncoding sequence, called CNS1 by Loots et al. (2000), is 401 bp in length and is located in the intergenic region, approximately 13 kb, between IL4 and IL13. CNS1 demonstrates a high degree of conservation across mammals (80% identity in mice, humans, cows, dogs, and rabbits), which contrasts sharply with the relatively low conservation observed in the coding regions of the flanking genes, IL4 and IL13, which have only 50% identity between humans and mice. This element is single copy in the human genome and has been conserved during evolution, not only with regard to sequence but also to genomic location, having been mapped in dogs, baboons, humans, and mice to the IL4-IL13 intergenic region. Experiments in transgenic mice revealed that CNS1 acts through its effect on the transcriptional activity of IL4, IL13, and IL5. Expression of other genes in the YAC had no change relative to wildtype in activated Th2 cells or other tissues tested.
By analysis of human YAC transgenic mice containing the 5q31 cytokine genes, Lacy et al. (2000) determined that the human proteins are produced under Th2 conditions in vitro and in response to Nippostrongylus brasiliensis, a Th2-inducing stimulus, in vivo. The authors observed no adverse effects on murine lymphoid organs. Fewer cells produced the endogenous mouse cytokines in transgenic than in control mice, suggesting competition for stable expression between the mouse and human genes. The data also suggested that regulatory elements within the human transgene are capable of interacting with trans-acting murine factors.
Fields et al. (2002) noted that high levels of histone acetylation at particular loci correlate with transcriptional activity, whereas reduced levels correlate with silencing. Using chromatin immunoprecipitation (ChIP), PCR, and green fluorescent protein analysis, they demonstrated that histones in the cytokine loci (IFNG, 147570; IL4) of naive T cells are unacetylated, but upon TCR stimulation, the loci are rapidly and progressively acetylated on histones H3 and H4. The acetylation at the IL4 locus occurs early, regardless of Th1/Th2 polarizing conditions, correlating with early transcription. The maintenance of acetylation depends on cytokine and STAT4 (600558) and STAT6 signaling and also on the transactivator activity of TBET (604895) and GATA3 (131320), the putative 'master regulators' of Th lineage determination.
Messi et al. (2003) showed that under conditions priming CD4-positive T cells to become either Th1 cells preferentially expressing a subset of cytokines, particularly IFNG, or Th2 cells expressing a different subset of cytokines, particularly IL4, naive and effector memory T cells acquire polarized cytokine gene acetylation patterns. They stated that commitment of T cells to either the Th1 or Th2 lineage requires upregulation of the fate-determining transcription factors TBET and GATA3, respectively. Whereas histone hyperacetylation of IFNG and IL4 promoters in Th1 and Th2 cells, respectively, was stable, central memory T cells had hypoacetylated cytokine genes that became hyperacetylated upon polarization after appropriate stimulation. However, all Th1 and most Th2 cells tested could express the alternative cytokine when stimulated under opposite Th conditions. Messi et al. (2003) concluded that most human CD4-positive T cells retain both memory and flexibility of cytokine gene expression.
Selective skewing of autoreactive IFNG-producing T helper cells (Th1) toward an IL4-producing (Th2) phenotype can in experimental animals alleviate autoimmune disease without producing general immunosuppression. In a prospective dose escalation study, Ghoreschi et al. (2003) assessed treatment with human IL4 in 20 patients with severe psoriasis (see 177900). The therapy was well tolerated, and within 6 weeks all patients showed decreased clinical scores and 15 improved more than 68%. Stable reduction of clinical scores was significantly better at 0.2 to 0.5 micrograms recombinant human IL4 than at less than 0.1 microgram (P = 0.009). In psoriatic lesions, treatment with 0.2-0.5 microgram/kilogram recombinant human IL4 reduced the concentrations of IL8 (146930) and IL19 (605687), 2 cytokines directly involved in psoriasis; the number of chemokine receptor CCR5+ (601373) Th1 cells; and the IFNG/IL4 ratio. In the circulation, 0.2-0.5 microgram/kilogram recombinant human IL4 increased the number of IL4+CD4+ T cells 2- to 3-fold. Thus, Ghoreschi et al. (2003) concluded that IL4 therapy can induce Th2 differentiation in human CD4+ T cells and has promise as a potential treatment for psoriasis.
Because IL4 and IL13 (147683) and their specific signaling pathways are considered attractive targets for the treatment of allergy and asthma, Kelly-Welch et al. (2003) reviewed the signaling connections of these cytokines. IL4 interacts with IL4R with high affinity, leading to dimerization with either the common gamma chain (IL2RG; 308380), a component of receptors for a number of cytokines, to create a type I receptor, or with IL13RA1 (300119) to form a type II receptor. IL13, on the other hand, binds with high affinity to IL13RA1, which induces heterodimerization with IL4R to form a complex identical to the type II receptor. Alternatively, IL13 may bind with even greater affinity to IL13RA2 (300130), which fails to induce a signal, indicating that it acts as a decoy receptor. The C-terminal tails of the IL4 and IL13 receptor subunits interact with tyrosine kinases of the Janus kinase family (e.g., JAK1; 147795), leading to interaction with STAT6, which binds to consensus sequences in the promoters of IL4- and IL13-regulated genes. Kelly-Welch et al. (2003) proposed that subtle differences in IL4 and IL13 signaling due to polymorphisms near docking sites in IL4R may have profound implications for allergy and asthma.
The transcription factor NFATC2 (600490) controls myoblast fusion at a specific stage of myogenesis after the initial formation of a myotube and is necessary for further cell growth. By examining genes regulated by NFATC2 in muscle, Horsley et al. (2003) identified the cytokine IL4 as a molecular signal that controls myoblast fusion with myotubes. Mouse muscle cells lacking Il4 or the Il4 receptor alpha subunit formed normally but were reduced in size and myonuclear number. Il4 was expressed by a subset of mouse muscle cells in fusing muscle cultures and required the Il4 receptor alpha subunit on myoblasts to promote fusion and growth. These data demonstrated that following myotube formation, myotubes recruit myoblast fusion by secretion of IL4, leading to muscle growth.
The T helper cell 1 and 2 (T(H)1 and T(H)2) pathways, defined by cytokines interferon-gamma (IFNG; 147570) and IL4, respectively, comprise 2 alternative CD4+ T-cell fates, with functional consequences for the host immune system. These cytokine genes are encoded on different chromosomes. The T(H)2 locus control region (LCR) coordinately regulates the T(H)2 cytokine genes by participating in a complex between the LCR and promoters of the cytokine genes IL4, IL5 (147850), and IL13. Although they are spread over 120 kb, these elements are closely juxtaposed in the nucleus in a poised chromatin conformation. In addition to these intrachromosomal interactions, Spilianakis et al. (2005) described interchromosomal interactions between the promoter region of the IFN-gamma gene on chromosome 10 and the regulatory regions of the T(H)2 cytokine locus on chromosome 11. DNase I hypersensitive sites that comprise the T(H)2 LCR developmentally regulate these interchromosomal interactions. Furthermore, there seems to be a cell type-specific dynamic interaction between interacting chromatin partners whereby interchromosomal interactions are apparently lost in favor of intrachromosomal ones upon gene activation. Thus, Spilianakis et al. (2005) provided an example of eukaryotic genes located on separate chromosomes associating physically in the nucleus via interactions that may have a function in coordinating gene expression.
Wu et al. (2011) showed that eosinophils are the major IL4-expressing cells in white adipose tissues of mice and, in their absence, alternatively activated macrophages are greatly attenuated. Eosinophils migrate into adipose tissue by an integrin-dependent process and reconstitute alternatively activated macrophages through an IL4- or IL13-dependent process. Mice fed a high-fat diet developed increased body fat, impaired glucose tolerance, and insulin resistance in the absence of eosinophils, and helminth-induced adipose tissue eosinophilia enhanced glucose tolerance. Wu et al. (2011) concluded that eosinophils may play an unexpected role in metabolic homeostasis through maintenance of adipose alternatively activated macrophages.
Nguyen et al. (2011) reported in mice an unexpected requirement for the IL4-stimulated program of alternative macrophage activation in adaptive thermogenesis. Exposure to cold temperature rapidly promoted alternative activation of adipose tissue macrophages, which secrete catecholamines to induce thermogenic gene expression in brown adipose tissue and lipolysis in white adipose tissue. Absence of alternatively activated macrophages impaired metabolic adaptations to cold, whereas administration of IL4 increased thermogenic gene expression, fatty acid mobilization, and energy expenditure, all in a macrophage-dependent manner. Thus Nguyen et al. (2011) concluded that they discovered a role for alternatively activated macrophages in the orchestration of an important mammalian stress response, the response to cold.
Reese et al. (2014) found that helminth infection, characterized by the induction of Il4 and the activation of Stat6 (601512), reactivated murine gamma-herpesvirus infection in vivo. Il4 promoted viral replication and blocked the antiviral effects of Ifng by inducing Stat6 binding to the promoter for an important viral transcriptional transactivator. Il4 also reactivated human Kaposi sarcoma-associated herpesvirus from latency in cultured cells. Exogenous Il4 plus blockade of Ifng reactivated latent murine gamma-herpesvirus infection in vivo, suggesting a '2-signal' model for viral reactivation. Thus, Reese et al. (2014) concluded that chronic herpesvirus infection, a component of the mammalian virome, is regulated by the counterpoised actions of multiple cytokines on viral promoters that have evolved to sense host immune status.
In the context of virus-helminth coinfection, Osborne et al. (2014) tested whether helminths induce potent immunomodulatory effects through direct regulation of host immunity or indirectly through eliciting changes in the microbiota. Helminth coinfection resulted in STAT6-dependent helminth-induced alternative activation of macrophages. Notably, helminth-induced impairment of antiviral immunity was evident in germ-free mice, but neutralization of Ym1, a chitinase-like molecule associated with alternatively activated macrophages, could partially restore antiviral immunity. Osborne et al. (2014) concluded that these data indicate that helminth-induced immunomodulation occurs independently of changes in the microbiota but is dependent on Ym1.
Bosurgi et al. (2017) showed that IL4 or IL13 (147683) alone was not sufficient, but IL4 or IL13 together with apoptotic cells, induced the tissue repair program in macrophages. Genetic ablation of sensors of apoptotic cells impaired the proliferation of tissue-resident macrophages and the induction of antiinflammatory and tissue repair genes in the lungs after helminth infection or in the gut after induction of colitis. By contrast, the recognition of apoptotic cells was dispensable for cytokine-dependent induction of pattern recognition receptor (CLEC7A; 606264), cell adhesion, or chemotaxis genes in macrophages. Detection of apoptotic cells can therefore spatially compartmentalize or prevent premature or ectopic activity of pleiotropic, soluble cytokines such as IL4 or IL13.
Minutti et al. (2017) discovered local tissue-specific amplifiers of type 2-mediated macrophage activation. In the lung, surfactant protein A (SPA; 178630) enhanced IL4-dependent macrophage proliferation and activation, accelerating parasite clearance and reducing pulmonary injury after infection with a lung-migrating helminth. In the peritoneal cavity and liver, C1q (120550) enhancement of type 2 macrophage activation was required for liver repair after bacterial infection, but resulted in fibrosis after peritoneal dialysis. Minutti et al. (2017) concluded that their data showed that IL4 drives production of the structurally related defense collagens SPA and C1q and the expression of their receptor, myosin 18A (610067), and that their findings revealed the existence within different tissues of an amplification system needed for local type 2 responses.
Using single-cell RNA sequencing in human and mouse non-small-cell lung cancers, Maier et al. (2020) identified a cluster of dendritic cells (DCs) that they named 'mature dendritic cells enriched in immunoregulatory molecules' (mregDCs), owing to their coexpression of immunoregulatory genes and maturation genes. Maier et al. (2020) found that the mregDC program is expressed by canonical DC1s and DC2s upon uptake of tumor antigens and further found that upregulation of PDL1 (605402), a key checkpoint molecule, in mregDCs is induced by the receptor tyrosine kinase AXL (109135), while upregulation of interleukin-12 (IL12; see 161560) depends strictly on interferon-gamma (IFNG; 147570) and is controlled negatively by IL4 signaling. Blocking IL4 enhances IL12 production by tumor antigen-bearing mregDC1s, expands the pool of tumor-infiltrating effector T cells, and reduces tumor burden. Maier et al. (2020) concluded that they uncovered a regulatory module associated with tumor-antigen uptake that reduces DC1 functionality in human and mouse cancers.
Crystal Structure
LaPorte et al. (2008) reported the crystal structures of the complete set of IL4 and IL13 type I (IL4RA/IL2RG/IL4) and type II (IL4RA/IL13RA1/IL4 and IL4RA/IL13RA1/IL13) ternary signaling complexes at the 3.0-angstrom level. They noted that the type I receptor complex is more active in regulating Th2 development, whereas the type II receptor complex is not found on T cells and is more active in regulating cells that mediate airway hypersensitivity and mucus secretion. The type I complex revealed a structural basis for the ability of IL2RG to recognize 6 different IL2RG cytokines.
Hunt et al. (2000) examined polymorphisms in the IL4 gene in Graves disease (GD; 275000) and autoimmune hypothyroidism (AIH). Analysis showed a reduced frequency of the variant T allele in the IL4 promoter polymorphism (-590C-T) in patients with GD and in the entire patient group (GD and AIH) compared with the control group. This was reflected in a reduction in the heterozygote genotype in the patient groups compared with the controls. The authors concluded that an IL4 variant, or a closely linked gene, has a modest protective effect against the development of autoimmune thyroid disease, particularly GD.
Based on previous studies of subacute sclerosing panencephalitis (SSPE; 260470) suggesting a preserved Th2 response and a defect of the Th1 response in patients with SSPE at the time of initial measles infection, Inoue et al. (2002) examined polymorphisms of Th1- and Th2-related cytokines to identify potential host factors involved in the development of SSPE. Inoue et al. (2002) found a significantly higher frequency of the IL4 promoter -589T (also known as -590) polymorphism in 38 Japanese patients with SSPE than in 100 healthy Japanese controls. In addition, this IL4 promoter allele was found in combination with an interferon regulatory factor-1 (IRF1; 147575) allele in patients with SSPE at a higher frequency than in controls. The authors suggested that in Japanese these polymorphisms contribute to host genetic factors that may predispose to the development of SSPE.
Kawashima et al. (1998) investigated linkage and association between gene markers on 5q31-33 and atopic dermatitis (see 603165) in 88 Japanese atopic dermatitis families. Affected sib pair analysis suggested linkage between the IL4 gene and atopic dermatitis (lod = 2.28). Transmission disequilibrium testing showed a significantly preferential transmission to atopic dermatitis offspring of the T allele of the -590C/T polymorphism of the IL4 gene (p = 0.001). A case-control comparison suggested a genotypic association of the T/T genotype with atopic dermatitis (odds ratio = 1.88, p = 0.01). Since the T allele may be associated with increased IL4 gene promoter activity compared with the C allele, Kawashima et al. (1998) suggested that genetic differences in transcriptional activity of the IL4 gene may influence atopic dermatitis predisposition.
Zee et al. (2004) collected DNA samples at baseline in a prospective cohort of 14,916 initially healthy American men. The authors then genotyped 92 polymorphisms from 56 candidate genes among 319 individuals who subsequently developed ischemic stroke and among 2,092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years. Two polymorphisms related to inflammation, val640-to-leu in the SELP gene (173610.0002) and a 582C-T transition in the IL4 gene, were found to be independent predictors of thromboembolic stroke (odds ratio of 1.63, P = 0.001, and odds ratio of 1.40, P = 0.003, respectively).
CD8+ cytotoxic T cells specific for the sporozoite stage of the malaria parasite (i.e., the stage injected from the Anopheles mosquito salivary glands) or specific for the circumsporozoite (CS) antigen protect mice against the development of liver-stage parasites. By depleting mice of CD4+ T cells, but not NK or NKT cells, and immunizing with sporozoites, Carvalho et al. (2002) showed that the mice initially retain but then lose the CD8+ T cell response. Using ELISPOT and flow cytometry/tetramer analysis on cells from mice with transgenic CD8+ cells specific for a CS antigen peptide, the authors determined that the maintenance of the CD8+ T cell response is dependent on CD4+ T cells. By a similar analysis in mice deficient in Stat6 (i.e., Th2-deficient), but not Stat4 (i.e., Th1-deficient), with confirmation in IL4 -/- mice or mice treated with anti-IL4, Carvalho et al. (2002) showed that the CD8+ T cell response depends on IL4 secreted by CD4+ T cells. They pointed out that it remained to be established whether the maintenance of the response is by a direct interaction of IL4 and CD8+ T cells or by the actions of IL4 on antigen-presenting cells or on IL4R+ T cells.
In addition to X-linked SCID (XSCID; 300400) caused by mutations in the common cytokine receptor gamma chain subunit (IL2RG), an autosomal form of SCID (600802) with T-cell deficiency occurs in patients with a mutation in the IL7R gene (146661). IL7 (146660) is vital for B-cell development in mice, but not in humans. Ozaki et al. (2002) developed a mouse model with a phenotype resembling human XSCID by knocking out the genes for both Il4 and Il21r (605383). Mice lacking only the Il21r gene had normal B- and T-cell phenotypes and functions, with the exception of lower IgG1 and IgG2b and higher serum IgE levels. After immunization with various antigens and with the parasite Toxoplasma gondii, the normal increase in IgG1 antibodies, as well as antigen-specific IgG2b and IgG3 antibodies, was significantly lower than in wildtype mice, and there was an uncharacteristic marked increase in antigen-specific IgE responses. In contrast, mice lacking both Il4 and Il21r exhibited lower levels of IgG and IgA, but not IgM, analogous to humans with XSCID. After immunization, these double-knockout mice did not upregulate IgE, indicating that this phenomenon is Il4-dependent, nor did they upregulate the IgG subclasses. The double-knockout mice, but not mice lacking only Il4 or Il21r, had disorganized germinal centers. Ozaki et al. (2002) proposed that defective signaling by IL4 and IL21 (605384) might explain the B-cell defect in XSCID.
In a study of Helicobacter infection (see 600263) and the immune response regulation of acid secretion, Zavros et al. (2003) demonstrated that treatment with the Th1 cytokine Ifng induced gastritis, increased gastrin (137250), and decreased somatostatin (182450) in mice, recapitulating changes seen with Helicobacter infection. In contrast, the Th2 cytokine Il4 increased somatostatin levels and suppressed gastrin expression and secretion. Il4 pretreatment prevented gastritis in infected wildtype but not in somatostatin-null mice. Immunofluorescence confirmed the presence of Il4 receptors (IL4R; 147781) on gastric somatostatin-secreting cells (D cells), and Il4 stimulated somatostatin release from primary D-cell cultures. Treatment of mice chronically infected with H. felis with a somatostatin analog resolved the inflammation. Zavros et al. (2003) concluded that IL4 resolves inflammation in the stomach by stimulating the release of somatostatin from gastric D cells.
Using mice lacking hypersensitivity site V (HS V), a 3-prime enhancer of the Il4 locus, Vijayanand et al. (2012) found that HS V was essential for IL4 production by follicular helper T (Tfh) cells. Mice with the HS V deletion also displayed defective type-2 humoral responses characterized by abrogated IgE and sharply reduced IgG1 production in vivo. Th2 cells involved in tissue responses were less dependent on HS V. Vijayanand et al. (2012) concluded that Tfh and Th2 cells use distinct but overlapping molecular mechanisms to regulate IL4.
Independently, Harada et al. (2012) reported findings similar to those of Vijayanand et al. (2012) in mice lacking HS V, which they called conserved noncoding sequence-2 (CNS2). Tracking of CNS2 activity with a GFP-reporter mouse demonstrated that CNS2-active cells, which were mainly localized in B-cell follicles and germinal centers, expressed numerous markers of Tfh cells, including Cxcr5 (601613), Pd1 (PDCD1; 600244), Icos (604558), Bcl6 (109565), Il21, and Il4. Harada et al. (2012) concluded that CNS2 is an essential enhancer element required for IL4 expression in Tfh cells, which control humoral immunity.
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