Alternative titles; symbols
HGNC Approved Gene Symbol: CCL11
Cytogenetic location: 17q12 Genomic coordinates (GRCh38): 17:34,285,742-34,288,334 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q12 | {Asthma, susceptibility to} | 600807 | Autosomal dominant | 3 |
| {HIV1, resistance to} | 609423 | 3 |
Chemoattractant cytokines (chemokines) play an important role in the recruitment of leukocytes to inflammatory lesions. Interleukin-8 (146930) is predominantly a neutrophil chemoattractant, whereas monocyte chemotactic protein-1 (MCP1, or CCL2; 158105) serves predominantly as a monocyte and T-cell chemoattractant. Ponath et al. (1996) noted that the striking accumulation of eosinophils in certain tissues, particularly in response to parasitic infection and also as a result of IGE-mediated reactions such as rhinitis and allergic asthma, suggests that there may be factors that are chemotactic specifically for eosinophils. The chemokine termed eotaxin was identified as the predominant eosinophil chemoattractant in bronchoalveolar lavage fluid of allergen-challenged guinea pigs. Ponath et al. (1996) cloned a human homolog of guinea pig eotaxin. Human eotaxin mediated the selective migration of eosinophils, both in vitro and in vivo. Human eotaxin was found to be 61.8% and 63.2% identical to guinea pig and mouse eotaxin, respectively. Radiolabeled eotaxin was used to identify a high-affinity receptor on eosinophils. This receptor also bound RANTES (187011) and monocyte chemotactic protein-3 (CCL7; 158106). The same gene was isolated by Kitaura et al. (1996), who showed that the recombinantly expressed protein induced a calcium flux response in human eosinophils but not in either neutrophils or monocytes. They showed that the response was mediated through the CC chemokine receptor-3 (CCR3; 601268), a G protein-coupled receptor expressed in eosinophils.
Eotaxin is a potent inducer of eosinophil chemotaxis leading to eosinophil migration in vitro and accumulation in vivo. These effects are mediated via CCR3, which is highly expressed on eosinophils, basophils, and TH2 lymphocytes and, thus, is involved in allergic inflammation. Ogilvie et al. (2001) showed that eotaxin also interacts with CCR2 (601267) and CCR5 (601373) and can thus affect the responses of monocytes, which express both receptors. In human monocytes, they found that pretreatment with eotaxin decreased responsiveness to MCP1, a selective ligand for CCR2, as well as to RANTES and MIP1-beta (182284), which bind to CCR5. These and other results from the study demonstrated that eotaxin is a CCR5 agonist and a CCR2 antagonist. The authors suggested that eotaxin has a role in the fine-tuning of cellular responses occurring at sites of allergic inflammation, in which both MCP1 and eotaxin are produced.
Salcedo et al. (2001) showed that CCL11 induces CCR3-expressing endothelial cell migration in vitro and angiogenesis in vivo, as well as endothelial cell sprouting from aortic rings in the absence of an eosinophil infiltrate. They suggested that CCL11 may contribute to angiogenesis in conditions accompanied by eosinophil infiltration such as Hodgkin lymphoma (236000), nasal polyposis, endometriosis, and allergic diathesis.
Menzies-Gow et al. (2002) used immunohistological analysis to examined the effects of intradermal injection of eotaxin and eotaxin-2 (CCL24; 602495), both of which act through CCR3, into human atopic and nonatopic skin. Both chemokines produced a dose- and time-dependent local eosinophilia of comparable intensity and an acute wheal and flare response regardless of atopy status. Basophils and neutrophils also accumulated at the injection sites. Menzies-Gow et al. (2002) concluded that the eosinophilic and inflammatory cell infiltrate induced by eotaxins is consistent with CC chemokine-induced mast cell degranulation.
Villeda et al. (2011) used heterochronic parabiosis to demonstrate that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. Villeda et al. (2011) identified chemokines, including CCL11, the plasma levels of which correlated with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy aging humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Villeda et al. (2011) concluded that the decline in neurogenesis and cognitive impairments observed during aging can be in part attributed to changes in blood-borne factors.
Hein et al. (1997) cloned SCYA11 genomic sequence, including the coding region and 3 kb of DNA immediately 5-prime of the coding region. The SCYA11 gene has 3 exons. The authors identified a number of consensus regulatory elements in the 5-prime flanking region of the SCYA11 gene that potentially regulate SCYA11 gene expression and/or mediate the effects of antiinflammatory drugs.
Kitaura et al. (1996) mapped the SCYA11 gene to chromosome 17 using a somatic cell hybrid DNA panel. By FISH, Garcia-Zepeda et al. (1997) mapped the SCYA11 gene to 17q21.1-q21.2.
The eotaxin gene family (eotaxin 1; eotaxin 2; and eotaxin 3, 604697) recruits and activates CCR3-bearing cells such as eosinophils, mast cells, and Th2 lymphocytes that play a major role in allergic disorders. Shin et al. (2003) genotyped a 721-member asthma (600807) cohort at 17 polymorphisms among the 3 eotaxin loci. Statistical analysis revealed that the eotaxin 2 +1272A-G G* allele showed significantly lower frequency in asthmatics than in normal healthy controls (0.14 vs 0.23, P = 0.002), and that distribution of the eotaxin 2 +1272A-G G* allele-containing genotypes was also much lower in asthmatics (26.3 vs 40.8%, P = 0.003). In addition, a nonsynonymous SNP in eotaxin 1, +123Ala to Thr, showed significant association with total serum IgE levels (P = 0.002-0.02) (see 147050). The effect of eotaxin 1 +123Ala to Thr on total serum IgE appeared in a gene dose-dependent manner. The authors suggested that the development of asthma may be associated with eotaxin 2 +1272A-G polymorphisms, and the susceptibility to high IgE production may be attributed to the eotaxin 1 +123Ala to Thr polymorphism. In an erratum, the authors noted that the first base of the translation start site of the eotaxin 2 genomic reference sequence had been denoted as +1, introducing some errors in the numbering of the eotaxin 2 SNPs.
Modi et al. (2003) identified 3 SNPs that formed a 31-kb haplotype (H7; see 601156.0001) spanning the CCL2-CCL7-CCL11 gene cluster on chromosome 17q. The SNPs and the H7 haplotype were significantly associated with protection from HIV-1 infection (see 609423).
Batra et al. (2007) analyzed 3 polymorphisms in the CCL11 gene and a hexanucleotide (GAAGGA)n repeat (601156.0002) located 10.9 kb upstream of the gene in 235 patients with asthma and 239 age-, sex-, and ethnically matched controls and in 230 families with asthma from northern India. The authors found a highly significant association of the hexanucleotide repeat with asthma (p = 3 x 10(-6)).
Modi et al. (2003) genotyped 9 SNPs spanning the CCL2 (158105)-CCL7 (158106)-CCL11 gene cluster on chromosome 17q in more than 3,000 DNA samples from 5 AIDS cohorts (see 609423). Extensive linkage disequilibrium was observed, particularly for 3 SNPs, -2136T in the CCL2 promoter (158105.0001), 767G in intron 1 of the CCL2 gene (158105.0002), and -1385A in the CCL11 promoter, that formed a 31-kb haplotype (H7) containing the 3 genes. The frequencies of these 3 SNPs and the H7 haplotype were significantly elevated in uninfected individuals repeatedly exposed to HIV-1 through high-risk sexual behavior or contaminated blood products. Since these chemokines do not bind the primary HIV-1 coreceptors CCR5 (601373) or CXCR4 (162643), Modi et al. (2003) proposed that the influence of the H7 haplotype on HIV-1 transmission may result from activation of the immune system rather than receptor blockage.
Batra et al. (2007) studied 235 patients with asthma (600807) and 239 age-, sex-, and ethnically matched controls and 230 families with asthma from northern India and found a significant association between a polymorphic hexanucleotide (GAAGGA)n repeat, located 10.9 kb upstream of the CCL11 gene, and asthma (p = 3 x 10(-6)). The hexanucleotide repeat was also associated with total serum IgE levels (p = 0.006) and eotaxin levels (p = 0.004).
Batra, J., Rajpoot, R., Ahluwalia, J., Devarapu, S. K., Sharma, S. K., Dinda, A. K., Ghosh, B. A hexanucleotide repeat upstream of eotaxin gene promoter is associated with asthma, serum total IgE and plasma eotaxin levels. (Letter) J. Med. Genet. 44: 397-403, 2007. [PubMed: 17220216] [Full Text: https://doi.org/10.1136/jmg.2006.046607]
Garcia-Zepeda, E. A., Rothenberg, M. E., Weremowicz, S., Sarafi, M. N., Morton, C. C., Luster, A. D. Genomic organization, complete sequence, and chromosomal location of the gene for human eotaxin (SCYA11), an eosinophil-specific CC chemokine. Genomics 41: 471-476, 1997. [PubMed: 9169149] [Full Text: https://doi.org/10.1006/geno.1997.4656]
Hein, H., Schluter, C., Kulke, R., Christophers, E., Schroder, J.-M., Bartels, J. Genomic organization, sequence, and transcriptional regulation of the human eotaxin gene. Biochem. Biophys. Res. Commun. 237: 537-542, 1997. [PubMed: 9299399] [Full Text: https://doi.org/10.1006/bbrc.1997.7169]
Kitaura, M., Nakajima, T., Imai, T., Harada, S., Combadiere, C., Tiffany, H. L., Murphy, P. M., Yoshie, O. Molecular cloning of human eotaxin, an eosinophil-selective CC chemokine, and identification of a specific eosinophil eotaxin receptor, CC chemokine receptor 3. J. Biol. Chem. 271: 7725-7730, 1996. [PubMed: 8631813] [Full Text: https://doi.org/10.1074/jbc.271.13.7725]
Menzies-Gow, A., Ying, S., Sabroe, I., Stubbs, V. L., Soler, D., Williams, T. J., Kay, A. B. Eotaxin (CCL11) and eotaxin-2 (CCL24) induce recruitment of eosinophils, basophils, neutrophils, and macrophages as well as features of early- and late-phase allergic reactions following cutaneous injection in human atopic and nonatopic volunteers. J. Immun. 169: 2712-2718, 2002. [PubMed: 12193745] [Full Text: https://doi.org/10.4049/jimmunol.169.5.2712]
Modi, W. S., Goedert, J. J., Strathdee, S., Buchbinder, S., Detels, R., Donfield, S., O'Brien, S. J., Winkler, C. MCP-1-MCP-3-eotaxin gene cluster influences HIV-1 transmission. AIDS 17: 2357-2365, 2003. [PubMed: 14571188] [Full Text: https://doi.org/10.1097/00002030-200311070-00011]
Ogilvie, P., Bardi, G., Clark-Lewis, I., Baggiolini, M., Uguccioni, M. Eotaxin is a natural antagonist for CCR2 and an agonist for CCR5. Blood 97: 1920-1924, 2001. [PubMed: 11264152] [Full Text: https://doi.org/10.1182/blood.v97.7.1920]
Ponath, P. D., Qin, S., Ringler, D. J., Clark-Lewis, I., Wang, J., Kassam, N., Smith, H., Shi, X., Gonzalo, J.-A., Newman, W., Gutierrez-Ramos, J.-C., Mackay, C. R. Cloning of the human eosinophil chemoattractant, eotaxin: expression, receptor binding, and functional properties suggest a mechanism for the selective recruitment of eosinophils. J. Clin. Invest. 97: 604-612, 1996. [PubMed: 8609214] [Full Text: https://doi.org/10.1172/JCI118456]
Salcedo, R., Young, H. A., Ponce, M. L., Ward, J. M., Kleinman, H. K., Murphy, W. J., Oppenheim, J. J. Eotaxin (CCL11) induces in vivo angiogenic responses by human CCR3+ endothelial cells. J. Immun. 166: 7571-7578, 2001. Note: Erratum: J. Immun. 168: 511 only, 2002. [PubMed: 11390513] [Full Text: https://doi.org/10.4049/jimmunol.166.12.7571]
Shin, H. D., Kim, L. H., Park, B. L., Jung, J. H., Kim, J. Y., Chung, I.-Y., Kim, J. S., Lee, J. H., Chung, S. H., Kim, Y. H., Park, H.-S., Choi, J. H., Lee, Y. M., Park, S. W., Choi, B. W., Hong, S.-J., Park, C.-S. Association of eotaxin gene family with asthma and serum total IgE. Hum. Molec. Genet. 12: 1279-1285, 2003. Note: Erratum: Hum. Molec. Genet. 12: 2083 only, 2003. [PubMed: 12761043] [Full Text: https://doi.org/10.1093/hmg/ddg142]
Villeda, S. A., Luo, J., Mosher, K. I., Zou, B., Britschgi, M., Bieri, G., Stan, T. M., Fainberg, N., Ding, Z., Eggel, A., Lucin, K. M., Czirr, E., and 11 others. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477: 90-94, 2011. [PubMed: 21886162] [Full Text: https://doi.org/10.1038/nature10357]