Alternative titles; symbols
HGNC Approved Gene Symbol: CCL20
Cytogenetic location: 2q36.3 Genomic coordinates (GRCh38): 2:227,813,842-227,817,556 (from NCBI)
Chemokines are a group of small (approximately 8-14 kD), mostly basic, structurally related molecules that regulate cell trafficking of various types of leukocytes through interactions with a subset of 7-transmembrane, G protein-coupled receptors. Chemokines also play fundamental roles in the development, homeostasis, and function of the immune system, and they have effects on cells of the central nervous system as well as on endothelial cells involved in angiogenesis or angiostasis. Chemokines are divided into 2 major subfamilies, CXC and CC, based on the arrangement of the first 2 of the 4 conserved cysteine residues; the 2 cysteines are separated by a single amino acid in CXC chemokines and are adjacent in CC chemokines. CXC chemokines are further subdivided into ELR and non-ELR types based on the presence or absence of a glu-leu-arg sequence adjacent and N terminal to the CXC motif (summary by Strieter et al., 1995; Zlotnik and Yoshie, 2000).
Hromas et al. (1997) reported the cloning and characterization of a novel human chemokine, which they termed 'Exodus' for its chemotactic properties. The full-length cDNA encodes a 95-amino acid polypeptide that includes a 22-amino acid putative signal sequence. This novel chemokine has approximately 28% homology with MIP-1-alpha (182283) and RANTES (187011), and shares several of their biologic activities. Exodus is expressed preferentially in lymphocytes and monocytes, and its expression is markedly upregulated by mediators of inflammation such as tumor necrosis factor (TNF; 191160) and lipopolysaccharide. Purified synthetic Exodus inhibited proliferation of myeloid progenitors in colony formation assays. Exodus also stimulated chemotaxis of peripheral blood mononuclear cells. The sequence homology, expression, and biologic activity indicated that Exodus represents a novel, divergent beta-chemokine.
Rossi et al. (1997) identified the Exodus chemokine, which they termed MIP-3-alpha for 'macrophage inflammatory protein-3-alpha.'
Nelson et al. (2001) identified 2 variants of CCL20 that are derived by use of alternative splice acceptor sites. One variant, isolated from myeloid leukemia cells, T lymphocytes, and lipopolysaccharide-stimulated monocyte RNA, contains an N-terminal alanine following removal of the signal sequence. The second variant, isolated from liver, contains an in-frame deletion of 3 bases that correspond to this alanine. The deletion results in a protein that is shorter by 1 amino acid and contains an N-terminal serine in the mature protein.
Using in situ hybridization and immunohistochemistry, Homey et al. (2000) demonstrated that MIP3A, or CCL20, and its receptor, CCR6 (601835), are markedly upregulated in psoriasis (see 177900) and that CCL20-expressing keratinocytes colocalize with CLA-positive (see PSGL1; 600738) skin-infiltrating T lymphocytes in lesional psoriatic skin. By flow cytometry analysis, they showed that circulating CLA-positive memory T cells in both normal and psoriatic individuals expressed high levels of surface CCR6, which was expressed 100- to 1,000-fold higher than other chemokine receptors on this T-cell subpopulation. CCL20 was chemotactic for CLA-positive T cells at lower concentrations in psoriatic than in normal donor lymphocytes. ELISA and RT-PCR analysis showed that multiple cellular constituents of the skin produce CCL20 in response to a variety of proinflammatory mediators, including TNF/IL1B (147720), CD40LG (300386), IFNG (147570), and IL17 (603149).
Nelson et al. (2001) assayed the activity of the alanine-CCL20 and serine-CCL20 splice variants toward several human peripheral blood leukocytes. These chemokines showed negligible activity toward neutrophils, monocytes, and naive T lymphocytes. However, flu antigen plus IL2 (147680)-activated CD4+ (186940), and CD8+ (186910) T lymphoblasts and cord blood-derived dendritic cells responded to both forms of CCL20. Both forms exerted a dose-dependent effect on recruitment of activated T cells and on intracellular calcium mobilization.
Reboldi et al. (2009) found that Ccr6-deficient mice were highly resistant to induction of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS; 126200), but became susceptible after transfer of small numbers of Ccr6-positive T cells. Ccr6 was required on the first wave of Il17 (603149)-producing T-helper cells (Th17 cells) entering the central nervous system (CNS) through Ccl20-expressing epithelial cells in the choroid plexus. The Ccr6-positive T cells triggered entry of a second wave of T cells that migrated in large numbers into the CNS by crossing activated parenchymal vessels. Reboldi et al. (2009) found that patients undergoing an initial demyelinating event (the first clinical episode of MS) had significantly higher frequencies of CCR6-positive/CD25 (IL2RA; 147730)-negative/CD4-positive inflammatory T cells in cerebrospinal fluid than in peripheral blood. MS patients expressed high levels of CCL20 in inflamed tissues, in GFAP (137780)-positive astrocytes, and in choroid plexus. Reboldi et al. (2009) proposed that CCR6 and CCL20 may represent an evolutionarily conserved axis that regulates the entry and dissemination of T cells into the CNS.
Nelson et al. (2001) determined that the CCL20 gene contains 4 exons. The promoter region contains a TATA box, a TFIID (313650)-binding site, overlapping AP2 (107580)-binding sites and an SV40 T antigen-binding site. Harant et al. (2001) identified a putative CAAT-box and other potential binding sites. By several criteria, they identified a functional NF-kappa-B (164014) element that responded to TNF-alpha stimulation. Kwon et al. (2003) identified a site that regulated both basal and cytokine-induced gene activation and bound the ETS nuclear factor ESE1 (ELF3; 602191).
By somatic cell hybridization and radiation hybrid analysis, Hieshima et al. (1997) mapped the CCL20 (formerly SCYA20) gene to chromosome 2q33-q37. By FISH, Nelson et al. (2001) mapped the gene to chromosome 2q35-q36.
Harant, H., Eldershaw, S. A, Lindley, I. J. Human macrophage inflammatory protein-3-alpha/CCL20/LARC/EXODUS/SCYA20 is transcriptionally upregulated by tumor necrosis factor-alpha via a non-standard NF-kappa-B site. FEBS Lett. 509: 439-445, 2001. [PubMed: 11749970] [Full Text: https://doi.org/10.1016/s0014-5793(01)03138-6]
Hieshima, K., Imai, T., Opdenakker, G., Van Damme, J., Kusuda, J., Tei, H., Sakaki, Y., Takatsuki, K., Miura, R., Yoshie, O., Nomiyama, H. Molecular cloning of a novel human CC chemokine liver and activation-regulated chemokine (LARC) expressed in liver: chemotactic activity for lymphocytes and gene localization on chromosome 2. J. Biol. Chem. 272: 5846-5853, 1997. [PubMed: 9038201] [Full Text: https://doi.org/10.1074/jbc.272.9.5846]
Homey, B., Dieu-Nosjean, M.-C., Wiesenborn, A., Massacrier, C., Pin, J.-J., Oldham, E., Catron, D., Buchanan, M. E., Muller, A., de Waal Malefyt, R., Deng, G., Orozco, R., Ruzicka, T., Lehmann, P., Lebecque, S., Caux, C., Zlotnik, A. Up-regulation of macrophage inflammatory protein-3-alpha/CCL20 and CC chemokine receptor 6 in psoriasis. J. Immun. 164: 6621-6632, 2000. [PubMed: 10843722] [Full Text: https://doi.org/10.4049/jimmunol.164.12.6621]
Hromas, R., Gray, P. W., Chantry, D., Godiska, R., Krathwohl, M., Fife, K., Bell, G. I., Takeda, J., Aronica, S., Gordon, M., Cooper, S., Broxmeyer, H. E., Klemsz, M. J. Cloning and characterization of Exodus, a novel beta-chemokine. Blood 89: 3315-3322, 1997. [PubMed: 9129037]
Kwon, J. H., Keates, S., Simeonidis, S., Grall, F., Libermann, T. A, Keates, A. C. ESE-1, an enterocyte-specific Ets transcription factor, regulates MIP-3-alpha gene expression in Caco-2 human colonic epithelial cells. J. Biol. Chem. 278: 875-884, 2003. [PubMed: 12414801] [Full Text: https://doi.org/10.1074/jbc.M208241200]
Nelson, R. T., Boyd, J., Gladue, R. P., Paradis, T., Thomas, R., Cunningham, A. C., Lira, P., Brissette, W. H., Hayes, L., Hames, L. M., Neote, K. S., McColl, S. R. Genomic organization of the CC chemokine MIP-3-alpha/CCL20/LARC/EXODUS/SCYA20, showing gene structure, splice variants, and chromosome localization. Genomics 73: 28-37, 2001. [PubMed: 11352563] [Full Text: https://doi.org/10.1006/geno.2001.6482]
Reboldi, A., Coisne, C., Baumjohann, D., Benvenuto, F., Bottinelli, D., Lira, S., Uccelli, A., Lanzavecchia, A., Engelhardt, B., Sallusto, F. C-C chemokine receptor 6-regulated entry of T(H)-17 cells into the CNS through choroid plexus is required for the initiation of EAE. Nature Immun. 10: 514-523, 2009. [PubMed: 19305396] [Full Text: https://doi.org/10.1038/ni.1716]
Rossi, D. L., Vicari, A. P., Franz-Bacon, K., McClanahan, T. K., Zlotnik, A. Identification through bioinformatics of two new macrophage proinflammatory human chemokines. J. Immun. 158: 1033-1036, 1997. Note: Erratum: J. Immun. 163: 1091 only, 1999. [PubMed: 9013939]
Strieter, R. M., Polverini, P. J., Arenberg, D. A., Kunkel, S. L. The role of CXC chemokines as regulators of angiogenesis. Shock 4: 155-160, 1995. [PubMed: 8574748] [Full Text: https://doi.org/10.1097/00024382-199509000-00001]
Zlotnik, A., Yoshie, O. Chemokines: a new classification system and their role in immunity. Immunity 12: 121-127, 2000. [PubMed: 10714678] [Full Text: https://doi.org/10.1016/s1074-7613(00)80165-x]