C-C chemokine receptor type 6 explained

Chemokine receptor 6 also known as CCR6 is a CC chemokine receptor protein which in humans is encoded by the CCR6 gene.^[1] CCR6 has also recently been designated CD196 (cluster of differentiation 196). The gene is located on the long arm of Chromosome 6 (6q27) on the Watson (plus) strand. It is 139,737 bases long and encodes a protein of 374 amino acids (molecular weight 42,494 Da).

Function

This protein belongs to family A of G protein-coupled receptor superfamily. The gene is expressed in lymphatic and non-lymphatic tissue as spleen, lymph nodes, pancreas, colon, appendix, small intestine. CCR6 is expressed on B-cells, immature dendritic cells (DC), T-cells (Th1, Th2, Th17, Treg), natural killer T cells (NKT cells) and neutrophils.^[2] The ligand of this receptor is CCL20 or in the other name - macrophage inflammatory protein 3 alpha (MIP-3 alpha). This chemokine receptor is special because it binds only one chemokine ligand CCL20 in compare to other chemokine receptors.^[3] CCR6 has a key role in connection between immature DC an adaptive immunity.^[4] This receptor has been shown to be important for B-lineage maturation and antigen-driven B-cell differentiation, and it may regulate the migration and recruitment of dendritic cells and T cells during inflammatory and immunological responses. Alternatively spliced transcript variants that encode the same protein have been described for this gene.^[5]

Interleukin 4 (IL-4) and interferon gamma (IFNγ) suppress expression of CCR6 in langerhans cells development and interleukin 10 (IL-10) induces the expression. It can regulate immune response in inflammatory tissue.^[6]

Proinflammatory Th17 cells express CCR6 and its ligand CCL20. CCR6 influences their migration to sites of inflammation. Some Th17 cells migrate via chemokine gradient of CCL20 to inflammatory sites and themselves can express more CCL20 to bring in more Th17 cells and regulatory T-cells (Treg). This can lead to chronic inflammation. In some models, the lack of CCR6 leads to less severe autoimmune encephalomyelitis.^[7]

Clinical significance

CCR6 has a function in development and metastatic spread of gastrointestinal malignancies.^[3] Expression of CCR6 was found to be up-regulated in colorectal cancer.^[8] Many patients with colorectal cancer have liver metastases. Colorectal carcinoma cells express CCR6 and CCL20. High level of CCL20 in liver chemoattract colorectal carcinoma cells and cause metastases in liver.^{[3] [9]} Novel research has identified a microRNA that is able to downregulate CCR6 in cancer cell lines.^[10]

CCR6 has been associated with Crohn's disease.^[11]

External links

• • Web site: Chemokine Receptors: CCR6 . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology .

Further reading

• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. . Gene . 138 . 1–2 . 171–4 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Zaballos A, Varona R, Gutiérrez J . Molecular cloning and RNA expression of two new human chemokine receptor-like genes . Biochem. Biophys. Res. Commun. . 227 . 3 . 846–53 . 1996 . 8886020 . 10.1006/bbrc.1996.1595 . etal.
• Liao F, Lee HH, Farber JM . Cloning of STRL22, a new human gene encoding a G-protein-coupled receptor related to chemokine receptors and located on chromosome 6q27 . Genomics . 40 . 1 . 175–80 . 1997 . 9070937 . 10.1006/geno.1996.4544 .
• Baba M, Imai T, Nishimura M . Identification of CCR6, the specific receptor for a novel lymphocyte-directed CC chemokine LARC . J. Biol. Chem. . 272 . 23 . 14893–8 . 1997 . 9169459 . 10.1074/jbc.272.23.14893 . etal. free .
• Wagner T, Tommerup N, Wirth J . A somatic cell hybrid panel for distal 17q: GDIA1 maps to 17q25.3 . Cytogenet. Cell Genet. . 76 . 3–4 . 172–5 . 1997 . 9186513 . 10.1159/000134538 . etal.
• Liao F, Alderson R, Su J . STRL22 is a receptor for the CC chemokine MIP-3alpha . Biochem. Biophys. Res. Commun. . 236 . 1 . 212–7 . 1997 . 9223454 . 10.1006/bbrc.1997.6936 . etal.
• Power CA, Church DJ, Meyer A . Cloning and characterization of a specific receptor for the novel CC chemokine MIP-3alpha from lung dendritic cells . J. Exp. Med. . 186 . 6 . 825–35 . 1997 . 9294137 . 10.1084/jem.186.6.825 . 2199050 . etal.
• Greaves DR, Wang W, Dairaghi DJ . CCR6, a CC chemokine receptor that interacts with macrophage inflammatory protein 3alpha and is highly expressed in human dendritic cells . J. Exp. Med. . 186 . 6 . 837–44 . 1997 . 9294138 . 10.1084/jem.186.6.837 . 2199049 . etal.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 . etal.
• Yang D, Chertov O, Bykovskaia SN . Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6 . Science . 286 . 5439 . 525–8 . 1999 . 10521347 . 10.1126/science.286.5439.525 . etal.
• Krzysiek R, Lefevre EA, Bernard J . Regulation of CCR6 chemokine receptor expression and responsiveness to macrophage inflammatory protein-3alpha/CCL20 in human B cells . Blood . 96 . 7 . 2338–45 . 2000 . 11001880 . 10.1182/blood.V96.7.2338. etal.
• Douglas GC, Thirkill TL, Sideris V . Chemokine receptor expression by human syncytiotrophoblast . J. Reprod. Immunol. . 49 . 2 . 97–114 . 2001 . 11164896 . 10.1016/S0165-0378(00)00083-8 . etal.
• Biragyn A, Surenhu M, Yang D . Mediators of innate immunity that target immature, but not mature, dendritic cells induce antitumor immunity when genetically fused with nonimmunogenic tumor antigens . J. Immunol. . 167 . 11 . 6644–53 . 2002 . 11714836 . 10.4049/jimmunol.167.11.6644. etal. free .
• Ebert LM, McColl SR . Up-regulation of CCR5 and CCR6 on distinct subpopulations of antigen-activated CD4+ T lymphocytes . J. Immunol. . 168 . 1 . 65–72 . 2002 . 11751947 . 10.4049/jimmunol.168.1.65. free .
• Liao F, Shirakawa AK, Foley JF . Human B cells become highly responsive to macrophage-inflammatory protein-3 alpha/CC chemokine ligand-20 after cellular activation without changes in CCR6 expression or ligand binding . J. Immunol. . 168 . 10 . 4871–80 . 2002 . 11994436 . 10.4049/jimmunol.168.10.4871. etal. free .
• Hosokawa Y, Nakanishi T, Yamaguchi D . Macrophage inflammatory protein 3alpha-CC chemokine receptor 6 interactions play an important role in CD4+ T-cell accumulation in periodontal diseased tissue . Clin. Exp. Immunol. . 128 . 3 . 548–54 . 2002 . 12067311 . 10.1046/j.1365-2249.2002.01865.x . 1906256 . etal.
• Kim CH, Johnston B, Butcher EC . Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among V alpha 24(+)V beta 11(+) NKT cell subsets with distinct cytokine-producing capacity . Blood . 100 . 1 . 11–6 . 2002 . 12070001 . 10.1182/blood-2001-12-0196 . 37076470 . free .
• Ai LS, Liao F . Mutating the four extracellular cysteines in the chemokine receptor CCR6 reveals their differing roles in receptor trafficking, ligand binding, and signaling . Biochemistry . 41 . 26 . 8332–41 . 2002 . 12081481 . 10.1021/bi025855y .
• Hoover DM, Boulegue C, Yang D . The structure of human macrophage inflammatory protein-3alpha /CCL20. Linking antimicrobial and CC chemokine receptor-6-binding activities with human beta-defensins . J. Biol. Chem. . 277 . 40 . 37647–54 . 2002 . 12149255 . 10.1074/jbc.M203907200 . etal. free .
• Maki W, Morales RE, Carroll VA . CCR6 colocalizes with CD18 and enhances adhesion to activated endothelial cells in CCR6-transduced Jurkat T cells . J. Immunol. . 169 . 5 . 2346–53 . 2002 . 12193700 . 10.4049/jimmunol.169.5.2346. etal. free .

Notes and References

1. Zaballos A, Varona R, Gutiérrez J, Lind P, Márquez G . Molecular cloning and RNA expression of two new human chemokine receptor-like genes . Biochem. Biophys. Res. Commun. . 227 . 3 . 846–53 . October 1996 . 8886020 . 10.1006/bbrc.1996.1595 .
2. Schutyser. Evemie. Struyf. Sofie. Van Damme. Jo. October 2003. The CC chemokine CCL20 and its receptor CCR6. Cytokine & Growth Factor Reviews. 14. 5. 409–426. 10.1016/s1359-6101(03)00049-2. 1359-6101. 12948524.
3. Frick. Vilma Oliveira. Rubie. Claudia. Keilholz. Ulrich. Ghadjar. Pirus. 2016-01-14. Chemokine/chemokine receptor pair CCL20/CCR6 in human colorectal malignancy: An overview. World Journal of Gastroenterology. 22. 2. 833–841. 10.3748/wjg.v22.i2.833. 2219-2840. 4716081. 26811629 . free .
4. Dieu. M. C.. Vanbervliet. B.. Vicari. A.. Bridon. J. M.. Oldham. E.. Aït-Yahia. S.. Brière. F.. Zlotnik. A.. Lebecque. S.. Caux. C.. 1998-07-20. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. The Journal of Experimental Medicine. 188. 2. 373–386. 10.1084/jem.188.2.373. 0022-1007. 2212459. 9670049.
5. Web site: Entrez Gene: CCR6 chemokine (C-C motif) receptor 6.
6. Dieu-Nosjean. Marie-Caroline. Massacrier. Catherine. Vanbervliet. Béatrice. Fridman. Wolf-Herman. Caux. Christophe. 2001-11-15. IL-10 Induces CCR6 Expression During Langerhans Cell Development While IL-4 and IFN-γ Suppress It. The Journal of Immunology. en. 167. 10. 5594–5602. 10.4049/jimmunol.167.10.5594. 11698430. 0022-1767. free.
7. Yamazaki. Tomohide. Yang. Xuexian O.. Chung. Yeonseok. Fukunaga. Atsushi. Nurieva. Roza. Pappu. Bhanu. Martin-Orozco. Natalia. Kang. Hong Soon. Ma. Li. Panopoulos. Athanasia D.. Craig. Suzanne. 2008-12-15. CCR6 Regulates the Migration of Inflammatory and Regulatory T Cells. The Journal of Immunology. en. 181. 12. 8391–8401. 10.4049/jimmunol.181.12.8391. 0022-1767. 2752441. 19050256.
8. Rubie. Claudia. Kruse. Bianca. Frick. Vilma Oliveira. Kölsch. Kathrin. Ghadjar. Pirus. Wagner. Mathias. Grässer. Friedrich. Wagenpfeil. Stefan. Glanemann. Mathias. 2014-02-21. Chemokine receptor CCR6 expression is regulated by miR-518a-5p in colorectal cancer cells. Journal of Translational Medicine. 12. 48. 10.1186/1479-5876-12-48. 1479-5876. 3996063. 24559209 . free .
9. Frick. V. O.. .Rubie. C.. Kölsch. K.. Wagner. M.. Ghadjar. P.. Graeber. S.. Glanemann. M.. September 2013. CCR6/CCL20 Chemokine Expression Profile in Distinct Colorectal Malignancies. Scandinavian Journal of Immunology. en. 78. 3. 298–305. 10.1111/sji.12087. 23790181. 45126701. free.
10. Rubie C. Feb 2014. Chemokine receptor CCR6 expression is regulated by miR-518a-5p in colorectal cancer cells.. J Transl Med. 12. 48. 10.1186/1479-5876-12-48. 3996063. 24559209 . free .
11. Wang K, Zhang H, Kugathasan S, Annese V, Bradfield JP, Russell RK, Sleiman PM, Imielinski M, Glessner J, Hou C, Wilson DC, Walters T, Kim C, Frackelton EC, Lionetti P, Barabino A, Van Limbergen J, Guthery S, Denson L, Piccoli D, Li M, Dubinsky M, Silverberg M, Griffiths A, Grant SF, Satsangi J, Baldassano R, Hakonarson H . Diverse Genome-wide Association Studies Associate the IL12/IL23 Pathway with Crohn Disease . Am. J. Hum. Genet. . 84. 3. 399–405. February 2009 . 19249008 . 10.1016/j.ajhg.2009.01.026 . 2668006 .