# CCL20

## Overview
CCL20 is a gene that encodes the protein C-C motif chemokine ligand 20, also known as macrophage inflammatory protein-3α (MIP-3α). This chemokine is a member of the chemokine family, which plays a pivotal role in the immune system by mediating the migration and positioning of immune cells. CCL20 is primarily involved in the chemotaxis of immune cells, such as dendritic cells, T-cells, and B-cells, through its interaction with the CCR6 receptor, a G protein-coupled receptor. The protein's structure, characterized by a unique N-terminal DCCL motif and a combination of β-sheets and α-helices, facilitates its specific binding to CCR6, influencing various physiological and pathological processes, including inflammation and cancer progression (Schutyser2003The; PérezCañadillas2001NMR). CCL20 is expressed in mucosal tissues and is upregulated in response to inflammatory stimuli, playing a significant role in maintaining mucosal homeostasis and contributing to the pathophysiology of diseases such as inflammatory bowel disease and multiple sclerosis (Thorley2005Primary; Kaser2004Increased). Additionally, the CCL20/CCR6 axis is implicated in cancer progression, with elevated levels of CCL20 associated with poor prognosis in various cancers (Chen2020CCL20; Kadomoto2020The).

## Structure
The CCL20 protein, also known as MIP-3α, is a chemokine characterized by a specific molecular structure that facilitates its interaction with the CCR6 receptor. The primary structure of CCL20 consists of a polypeptide chain with a unique N-terminal DCCL motif, which is crucial for its receptor specificity (PérezCañadillas2001NMR). The secondary structure includes a three-stranded antiparallel β-sheet and a C-terminal α-helix, with a 3_10 helix preceding the β-sheet (PérezCañadillas2001NMR). 

The tertiary structure of CCL20 is defined by a rigid conformation, particularly in the N-terminal region, which is stabilized by disulfide bonds and hydrogen bonds. This structure forms a narrow groove between the N-loop and the β2-β3 hairpin, contributing to its specific binding to CCR6 (PérezCañadillas2001NMR). The hydrophobic core of the protein is composed of side chains from the α-helix, β-sheet, and N-loop, with some hydrophobic residues exposed and well-ordered (PérezCañadillas2001NMR).

In terms of quaternary structure, CCL20 exists in a monomer-dimer equilibrium, with dimerization potentially involving the first β-strand of each monomer forming a six-stranded antiparallel sheet (PérezCañadillas2001NMR).

## Function
CCL20, also known as C-C motif chemokine ligand 20, is a chemokine involved in the immune response by attracting immune cells to sites of inflammation or infection. It primarily interacts with the CCR6 receptor, which is expressed on various immune cells, including immature dendritic cells, effector/memory T-cells, and B-cells. This interaction is crucial for the chemotaxis of these cells, facilitating their migration to areas where immune responses are needed, such as mucosal surfaces and inflamed tissues (Schutyser2003The).

In healthy human cells, CCL20 is constitutively expressed at low levels in mucosal tissues, such as the pulmonary epithelium, to maintain mucosal homeostasis by ensuring the constant recruitment of inflammatory cells. This is important for responding to continuous antigen challenges (Thorley2005Primary). The chemokine is also inducible under inflammatory conditions, with its expression upregulated by proinflammatory cytokines like IL-1β and TNF-α, as well as by bacterial endotoxins (Fujiie2001Proinflammatory; Hosokawa2005Increase).

CCL20's role extends to the recruitment of dendritic cells to the lung, where it is produced by alveolar type II epithelial cells. This production is crucial for the migration of monocyte-derived dendritic cells, highlighting its role in immune surveillance and response in the respiratory system (Thorley2005Primary).

## Clinical Significance
Alterations in the expression of the CCL20 gene have been implicated in several diseases. In inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, increased expression of CCL20 mRNA and protein is observed in colonic tissues. This upregulation is associated with the recruitment of CCR6+ memory T lymphocytes and immature dendritic cells to the mucosa, contributing to the disease's pathophysiology (Kaser2004Increased). 

In multiple sclerosis (MS), particularly in Egyptian patients, higher serum levels of CCL20 are linked to the disease's progression. Specific polymorphisms in the CCL20 gene, such as the rs6749704 polymorphism, are associated with increased susceptibility to MS, suggesting a genetic predisposition influenced by CCL20 (El2019The).

CCL20 is also involved in cancer progression. In gastric adenocarcinoma, the CCL20/CCR6 axis promotes immune suppression, facilitating tumor growth. High levels of CCL20 are associated with poor prognosis and increased tumor aggressiveness in various cancers, including hepatocellular carcinoma, breast cancer, and colorectal cancer (Liu2023PPARδ; Chen2020CCL20; Kadomoto2020The). In lung adenocarcinoma, elevated CCL20 expression correlates with worse survival outcomes and is linked to gefitinib resistance (Mao2021Identification).

## Interactions
CCL20, also known as macrophage inflammatory protein-3α (MIP-3α), primarily interacts with the chemokine receptor CCR6, a G protein-coupled receptor. This interaction is crucial for various physiological and pathological processes, including immune response and cancer progression. The binding of CCL20 to CCR6 involves a specific ionic interaction between the N-terminal amino group of CCL20 and the CCR6 side-chain E198, which disrupts the hydrogen bond network stabilizing CCR6 in its inactive state, facilitating receptor activation and G protein coupling (Wasilko2020Structural).

In cancer, CCL20 is implicated in promoting tumor growth and adhesion by enhancing the proliferation and survival of CCR6-expressing tumor cells, such as prostate cancer cells (PC3) and colon cancer cells (HT-29). This interaction is dose-dependent and involves G-protein coupled receptor signaling, as evidenced by the inhibition of adhesion by pertussis toxin (Beider2009Interaction). CCL20 also interacts with CXCR4, another chemokine receptor, in cancer cells, suggesting a regulatory role in CCL20 expression and function (Beider2009Interaction).

In addition to its role in cancer, CCL20 has been engineered into a dimeric form, CCL20 S64C, which acts as a partial agonist for CCR6. This engineered variant binds CCR6 with lower affinity and inhibits T cell chemotaxis, offering potential therapeutic applications in inflammatory diseases like psoriasis (Getschman2017Protein).


## References


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[2. (Schutyser2003The) Evemie Schutyser, Sofie Struyf, and Jo Van Damme. The cc chemokine ccl20 and its receptor ccr6. Cytokine & Growth Factor Reviews, 14(5):409–426, October 2003. URL: http://dx.doi.org/10.1016/s1359-6101(03)00049-2, doi:10.1016/s1359-6101(03)00049-2. This article has 599 citations.](https://doi.org/10.1016/s1359-6101(03)00049-2)

[3. (Wasilko2020Structural) David Jonathan Wasilko, Zachary Lee Johnson, Mark Ammirati, Ye Che, Matthew C. Griffor, Seungil Han, and Huixian Wu. Structural basis for chemokine receptor ccr6 activation by the endogenous protein ligand ccl20. Nature Communications, June 2020. URL: http://dx.doi.org/10.1038/s41467-020-16820-6, doi:10.1038/s41467-020-16820-6. This article has 81 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-020-16820-6)

[4. (Kadomoto2020The) Suguru Kadomoto, Kouji Izumi, and Atsushi Mizokami. The ccl20-ccr6 axis in cancer progression. International Journal of Molecular Sciences, 21(15):5186, July 2020. URL: http://dx.doi.org/10.3390/ijms21155186, doi:10.3390/ijms21155186. This article has 167 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/ijms21155186)

[5. (Chen2020CCL20) Weilong Chen, Yuanyuan Qin, and Suling Liu. CCL20 Signaling in the Tumor Microenvironment, pages 53–65. Springer International Publishing, 2020. URL: http://dx.doi.org/10.1007/978-3-030-36667-4_6, doi:10.1007/978-3-030-36667-4_6. This article has 49 citations.](https://doi.org/10.1007/978-3-030-36667-4_6)

[6. (Mao2021Identification) Kailin Mao, Fang Lin, Yingai Zhang, and Hailong Zhou. Identification of key genes and pathways in gefitinib-resistant lung adenocarcinoma using bioinformatics analysis. Evolutionary Bioinformatics, 17:117693432110237, January 2021. URL: http://dx.doi.org/10.1177/11769343211023767, doi:10.1177/11769343211023767. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.1177/11769343211023767)

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[9. (El2019The) Fathia Z. El Sharkawi, Sahar A. Ali, Mohamed I. Hegazy, and Hanaa B. Atya. The combined effect of il-17f and ccl20 gene polymorphism in susceptibility to multiple sclerosis in egypt. Gene, 685:164–169, February 2019. URL: http://dx.doi.org/10.1016/j.gene.2018.11.006, doi:10.1016/j.gene.2018.11.006. This article has 14 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.gene.2018.11.006)

[10. (Kaser2004Increased) Arthur Kaser, Othmar Ludwiczek, Sandra Holzmann, Alexander R. Moschen, Günter Weiss, Barbara Enrich, Ivo Graziadei, Stefan Dunzendorfer, Christian J. Wiedermann, Elisabeth Mürzl, Eveline Grasl, Zerina Jasarevic, Nikolaus Romani, Felix A. Offner, and Herbert Tilg. Increased expression of ccl20 in human inflammatory bowel disease. Journal of Clinical Immunology, 24(1):74–85, January 2004. URL: http://dx.doi.org/10.1023/B:JOCI.0000018066.46279.6b, doi:10.1023/b:joci.0000018066.46279.6b. This article has 242 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1023/B:JOCI.0000018066.46279.6b)

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[13. (Hosokawa2005Increase) Y Hosokawa, I Hosokawa, K Ozaki, H Nakae, and T Matsuo. Increase of ccl20 expression by human gingival fibroblasts upon stimulation with cytokines and bacterial endotoxin. Clinical and Experimental Immunology, 142(2):285–291, September 2005. URL: http://dx.doi.org/10.1111/j.1365-2249.2005.02912.x, doi:10.1111/j.1365-2249.2005.02912.x. This article has 52 citations and is from a peer-reviewed journal.](https://doi.org/10.1111/j.1365-2249.2005.02912.x)

[14. (Liu2023PPARδ) Yi Liu, Daoyan Wei, Yasunori Deguchi, Weiguo Xu, Rui Tian, Fuyao Liu, Min Xu, Fei Mao, Donghui Li, Weidong Chen, Lovie Ann Valentin, Eriko Deguchi, James C. Yao, Imad Shureiqi, and Xiangsheng Zuo. Pparδ dysregulation of ccl20/ccr6 axis promotes gastric adenocarcinoma carcinogenesis by remodeling gastric tumor microenvironment. Gastric Cancer, 26(6):904–917, August 2023. URL: http://dx.doi.org/10.1007/s10120-023-01418-w, doi:10.1007/s10120-023-01418-w. This article has 5 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s10120-023-01418-w)