Alternative titles; symbols
HGNC Approved Gene Symbol: IL5
Cytogenetic location: 5q31.1 Genomic coordinates (GRCh38): 5:132,541,445-132,556,815 (from NCBI)
Campbell et al. (1987) cloned eosinophil differentiation factor (EDF) from a genomic library in lambda phage by using a murine EDF cDNA clone as a probe. The predicted amino acid sequence of 134 amino acids was identical to that reported for human interleukin-5 but showed no significant homology with other known hematopoietic growth regulators. Interleukin-5 is a selective eosinophil-activating growth hormone. The amino acid sequence was about 70% identical to that of murine EDF. Recombinant human EDF, expressed from the human EDF gene after transfection into monkey COS cells, stimulated the production of eosinophils and eosinophil colonies from normal human bone marrow but had no effect on the production of neutrophils or mononuclear cells (monocytes and lymphoid cells).
Tanabe et al. (1987) cloned the IL5 gene and determined its structure.
Yokota et al. (1987) concluded that a single cDNA clone encodes a protein that acts as a growth and differentiation factor for both B cells and eosinophils.
Campbell et al. (1987) found that the human IL5 gene contains 3 introns.
Takahashi et al. (1989) mapped the IL5 gene to 5q23.3-q31.1 by in situ hybridization. Sutherland et al. (1988) assigned the gene to 5q31 by in situ hybridization and showed that the gene is deleted in the 5q- syndrome. At least 3 other genes involved in hematopoiesis are located in the same region: IL3 (147740), GMCSF (138960), and FMS (164770). Chandrasekharappa et al. (1990) demonstrated that IL4 and IL5 are closely linked physically, with a maximum separation of 310 kb. There appeared to be an HTF island between them. IL3 and CSF2 (138960), which are located in the same general area of 5q, could not physically be linked to IL4 or IL5. Willman et al. (1993), who mapped IRF1 (147575) to 5q31.1, concluded that the order of genes is: cen--IL4--IL5--IRF1--CDC25C--IL3/CSF2--tel. Kozak (1988) assigned the homologous mouse locus to chromosome 11 by in situ hybridization.
Coffman et al. (1989) showed that a monoclonal antibody to IL5 completely suppressed the blood eosinophilia in mice parasitized by a nematode but had no effect on serum IgE increase in response to the infestation. In contrast, an antibody to interleukin-4 (147780) inhibited parasite-induced IgE but not the eosinophilia.
In a patient with the hypereosinophilia syndrome (see 131400), Cogan et al. (1994) demonstrated clonal proliferation of type-2 helper T cells and showed that production of large amounts of IL5 was responsible for eosinophilia, and interleukin-4 for excessive production of IgE.
Studying 30 asthmatic and 30 nonasthmatic subjects, Pereira et al. (1998) found no changes from the normal sequence in all 4 exons of IL5, as well as the promoter and 3-prime untranslated regions, by SSCP and heteroduplex analysis. They concluded that mutations in the IL5 gene are not likely to be a common cause of inherited predisposition to asthma.
Simon et al. (1999) found that clonal populations of abnormal T cells producing interleukin-5 occur in some patients with idiopathic eosinophilia. Among 60 patients with idiopathic eosinophilia, 16 had circulating T cells with an aberrant immunophenotype. In each of these patients, the abnormal immunophenotype was unique. Evidence of clonal rearrangements of the T-cell receptor was obtained in 8 of the 16 patients. The aberrant T cells produced large amounts of interleukin-5 in vitro. At the time of the initial blood analysis, 15 of the 16 patients had no evidence of a malignant lymphoproliferative disorder.
Broide et al. (1999) reviewed the genes that regulate eosinophilic inflammation, including IL5.
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 (147683), 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 regards 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.
Normal intestinal mucosa contains abundant immunoglobulin A (IgA)-secreting cells, which are generated from B cells in gut-associated lymphoid tissues. Mora et al. (2006) showed that dendritic cells (DCs) from gut-associated lymphoid tissues induce T cell-independent expression of IgA and gut-homing receptors on B cells. Gut-associated lymphoid tissue DC-derived retinoic acid alone conferred gut tropism but could not promote IgA secretion. However, retinoic acid potently synergized with the gut-associated lymphoid tissue DC-derived IL6 (147620) or IL5 to induce IgA secretion. Mora et al. (2006) found that consequently, mice deficient in the retinoic acid precursor vitamin A lacked IgA-secreting cells in the small intestine. Mora et al. (2006) found that gut-associated lymphoid tissue DCs shape mucosal immunity by modulating B cell migration and effector activity through synergistically acting mediators.
Endo et al. (2011) examined expression of cell surface markers to identify functionally distinct subpopulations of mouse Th2 cells. FACS analysis demonstrated 4 Th2 subpopulations based on high or low expression levels of Cd62l (SELL; 153240) and Cxcr3 (300574). All 4 subpopulations produced comparable levels of Il4 and Il13, but Th2 cells expressing low levels of both Cd62l and Cxcr3 (Cd62l-lo/Cxcr3-lo cells) selectively produced Il5. Il5 production in Cd62l-lo/Cxcr3-lo cells was accompanied by histone H3-K4 methylation, a marker for the permissive conformation of chromatin, at the IL5 promoter. DNA microarray analysis and quantitative RT-PCR showed that Cd44 (107269)-positive memory Th2 cells expressing Il5 had lower levels of Eomes (604615) and Tbx21 (604895) and higher levels of Rora (600825) and Pparg (601487) than memory Th2 cells lacking Il5 expression. RNA silencing demonstrated that Eomes downregulation was required for Il5 expression and that Eomes had no effect on H3-K4 methylation at the Il5 promoter. Instead Eomes suppressed Gata3 (131320) transcriptional activity by inhibiting Gata3 binding to the Il5 promoter. Depletion of Cd62l-lo/Cxcr3-lo cells ameliorated memory Th2 cell-dependent airway inflammation in mice. Endo et al. (2011) concluded that IL5 production preferentially occurs in the CD62L-lo/CXCR3-lo subpopulation regulated by EOMES expression.
Nussbaum et al. (2013) showed that serum IL5 levels are maintained by long-lived type 2 innate lymphoid (ILC2) cells resident in peripheral tissues. ILC2 cells secrete IL5 constitutively and are induced to coexpress IL13 during type 2 inflammation, resulting in localized eotaxin (see 601156) production and eosinophil accumulation. In the small intestine where eosinophils and eotaxin are constitutive, ILC2 cells coexpress IL5 and IL13; this coexpression is enhanced after caloric intake. The circadian synchronizer vasoactive intestinal peptide (VIP; 192320) also stimulates ILC2 cells through the VPAC2 receptor (VIPR2; 601970) to release IL5, linking eosinophil levels with metabolic cycling. Tissue ILC2 cells regulate basal eosinophilopoiesis and tissue eosinophil accumulation through constitutive and stimulated cytokine expression, and this dissociated regulation can be tuned by nutrient intake and central circadian rhythms.
Rodrigues et al. (1996) noted that, as the main regulator of eosinopoiesis, eosinophil maturation and activation, and IgA production, IL5 contributes in several ways to human immune defenses against various pathogens, including helminths and infectious agents of the digestive and respiratory tracts. On the other hand, the increase in number of eosinophils and the activation of these cells, both of which are related to elevated IL5 production, are the cause of severe pathologic disorders, as in asthma or hypereosinophilic syndromes. To investigate the role of genetic factors in the large variability observed in IL5 production among subjects exposed to comparable antigenic stimulation, Rodrigues et al. (1996) conducted a segregation analysis in a Brazilian population infected by the helminth parasite Schistosoma mansoni. The analysis was performed on IL5 levels produced by blood mononuclear cells of these subjects after in vitro restimulation with either parasite extracts (designated IL5/SS for schistosomula sonicates) or the T-lymphocyte mitogen phytohemagglutinin (designated the IL5/PHA phenotype). The results provided evidence to Rodrigues et al. (1996) for the segregation of a codominant major gene controlling IL5/SS and IL5/PHA production and accounting for 70% and 73% of the phenotypic variance, respectively; the frequency of the allele predisposing to low IL5 production was approximately 0.22 for both phenotypes. They found no significant relationship between these genes and the gene controlling infection intensities by S. mansoni detected in a previous study. The authors could not ascertain whether the IL5/SS and IL5/PHA phenotypes were determined by a single gene locus.
The SM1 locus (181460) on chromosome 5q31-q33 is associated with intensity of infection with the African Schistosoma (blood fluke) species, S. mansoni. Ellis et al. (2007) genotyped 30 HapMap tagging SNPs in a nested case control study across 3 genes in the 5q31-q33 region, IL4, IL5, and IL13, in 159 individuals putatively susceptible to reinfection with the Asian Schistosoma species, S. japonicum, 133 putatively resistant individuals, and 113 individuals with symptomatic infection. They identified 2 strongly linked SNPs in the 3-prime UTR of IL5, rs4143832 and rs17690122, that were associated with susceptibility to symptomatic infection. Ellis et al. (2007) concluded that variants in the 3-prime UTR of IL5 may modulate the immune response in individuals with symptomatic infection.
Broide, D. H., Hoffman, H., Sriramarao, P. Genes that regulate eosinophilic inflammation. Am. J. Hum. Genet. 65: 302-307, 1999. [PubMed: 10417272] [Full Text: https://doi.org/10.1086/302520]
Campbell, H. D., Tucker, W. Q. J., Hort, Y., Martinson, M. E., Mayo, G., Clutterbuck, E. J., Sanderson, C. J., Young, I. G. Molecular cloning, nucleotide sequence, and expression of the gene encoding human eosinophil differentiation factor (interleukin-5). Proc. Nat. Acad. Sci. 84: 6629-6633, 1987. [PubMed: 3498940] [Full Text: https://doi.org/10.1073/pnas.84.19.6629]
Chandrasekharappa, S. C., Rebelsky, M. S., Firak, T. A., Le Beau, M. M., Westbrook, C. A. A long-range restriction map of the interleukin-4 and interleukin-5 linkage group on chromosome 5. Genomics 6: 94-99, 1990. [PubMed: 2303264] [Full Text: https://doi.org/10.1016/0888-7543(90)90452-z]
Coffman, R. L., Seymour, B. W. P., Hudak, S., Jackson, J., Rennick, D. Antibody to interleukin-5 inhibits helminth-induced eosinophilia in mice. Science 245: 308-310, 1989. [PubMed: 2787531] [Full Text: https://doi.org/10.1126/science.2787531]
Cogan, E., Schandene, L., Crusiaux, A., Cochaux, P., Velu, T., Goldman, M. Clonal proliferation of type 2 helper T cells in a man with the hypereosinophilic syndrome. New Eng. J. Med. 330: 535-538, 1994. [PubMed: 8302319] [Full Text: https://doi.org/10.1056/NEJM199402243300804]
Ellis, M. K., Zhao, Z. Z., Chen, H.-G., Montgomery, G. W., Li, Y.-S., McManus, D. P. Analysis of the 5q31-33 locus shows an association between single nucleotide polymorphism variants in the IL-5 gene and symptomatic infection with the human blood fluke, Schistosoma japonicum. J. Immun. 179: 8366-8371, 2007. [PubMed: 18056382] [Full Text: https://doi.org/10.4049/jimmunol.179.12.8366]
Endo, Y., Iwamura, C., Kuwahara, M., Suzuki, A., Sugaya, K., Tumes, D. J., Tokoyoda, K., Hosokawa, H., Yamashita, M., Nakayama, T. Eomesodermin controls interleukin-5 production in memory T helper 2 cells through inhibition of activity of the transcription factor GATA3. Immunity 35: 733-745, 2011. [PubMed: 22118525] [Full Text: https://doi.org/10.1016/j.immuni.2011.08.017]
Kozak, C. Personal Communication. Bethesda, Md. 6/9/1988.
Lacy, D. A., Wang, Z.-E., Symula, D. J., McArthur, C. J., Rubin, E. M., Frazer, K. A., Locksley, R. M. Faithful expression of the human 5q31 cytokine cluster in transgenic mice. J. Immun. 164: 4569-4574, 2000. [PubMed: 10779759] [Full Text: https://doi.org/10.4049/jimmunol.164.9.4569]
Loots, G. G., Locksley, R. M., Blankespoor, C. M., Wang, Z. E., Miller, W., Rubin, E. M., Frazer, K. A. Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science 288: 136-140, 2000. [PubMed: 10753117] [Full Text: https://doi.org/10.1126/science.288.5463.136]
Mora, J. R., Iwata, M., Eksteen, B., Song, S.-Y., Junt, T., Senman, B., Otipoby, K. L., Yokota, A., Takeuchi, H., Ricciardi-Castagnoli, P., Rajewsky, K., Adams, D. H., von Andrian, U. H. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314: 1157-1160, 2006. [PubMed: 17110582] [Full Text: https://doi.org/10.1126/science.1132742]
Nussbaum, J. C., Van Dyken, S. J., von Moltke, J., Cheng, L. E., Mohapatra, A., Molofsky, A. B., Thornton, E. E., Krummel, M. F., Chawla, A., Liang, H.-E., Locksley, R. M. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502: 245-248, 2013. [PubMed: 24037376] [Full Text: https://doi.org/10.1038/nature12526]
Pereira, E., Goldblatt, J., Rye, P., Sanderson, C., Le Souef, P. Mutation analysis of interleukin-5 in an asthmatic cohort. Hum. Mutat. 11: 51-54, 1998. [PubMed: 9450903] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1998)11:1<51::AID-HUMU8>3.0.CO;2-O]
Rodrigues, V., Jr., Abel, L., Piper, K., Dessein, A. J. Segregation analysis indicates a major gene in the control of interleukin-5 production in humans infected with Schistosoma mansoni. Am. J. Hum. Genet. 59: 453-461, 1996. [PubMed: 8755934]
Simon, H. U., Plotz, S. G., Dummer, R., Blaser, K. Abnormal clones of T cells producing interleukin-5 in idiopathic eosinophilia. New Eng. J. Med 341: 1112-1120, 1999. [PubMed: 10511609] [Full Text: https://doi.org/10.1056/NEJM199910073411503]
Sutherland, G. R., Baker, E., Callen, D. F., Campbell, H. D., Young, Y. G., Sanderson, C. J., Garson, O. M., Lopez, A. F., Vadas, M. A. Interleukin-5 is at 5q31 and is deleted in the 5q- syndrome. Blood 71: 1150-1152, 1988. [PubMed: 3258537]
Takahashi, M., Yoshida, M. C., Satoh, H., Hilgers, J., Yaoita, Y., Honjo, T. Chromosomal mapping of the mouse IL-4 and human IL-5 genes. Genomics 4: 47-52, 1989. [PubMed: 2563351] [Full Text: https://doi.org/10.1016/0888-7543(89)90313-3]
Tanabe, T., Konishi, M., Mizuta, T., Noma, T., Honjo, T. Molecular cloning and structure of the human interleukin-5 gene. J. Biol. Chem. 262: 16580-16584, 1987. [PubMed: 2824500]
Willman, C. L., Sever, C. E., Pallavicini, M. G., Harada, H., Tanaka, N., Slovak, M. L., Yamamoto, H., Harada, K., Meeker, T. C., List, A. F., Taniguchi, T. Deletion of IRF-1, mapping to chromosome 5q31.1, in human leukemia and preleukemic myelodysplasia. Science 259: 968-971, 1993. [PubMed: 8438156] [Full Text: https://doi.org/10.1126/science.8438156]
Yokota, T., Coffman, R. L., Hagiwara, H., Rennick, D. M., Takebe, Y., Yokota, K., Gemmell, L., Shrader, B., Yang, G., Meyerson, P., Luh, J., Hoy, P., Pene, J., Briere, F., Spits, H., Banchereau, J., de Vries, J., Lee, F. D., Arai, N., Arai, K. Isolation and characterization of lymphokine cDNA clones encoding mouse and human IgA-enhancing factor and eosinophil colony-stimulating factor activities: relationship to interleukin 5. Proc. Nat. Acad. Sci. 84: 7388-7392, 1987. [PubMed: 2823259] [Full Text: https://doi.org/10.1073/pnas.84.21.7388]