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Chemokine (C-C motif) ligand 1 (CCL1) is also known as small inducible cytokine A1 and I-309 in humans. CCL1 is a small glycoprotein that belongs to the CC chemokine family.

Genomics

CCL1 is encoded by CCL1 gene which is one of the several chemokine genes clustered on the chromosome 17q11.2-q12 in humans. It is expressed by specifically activated T cells upon secondary stimulation. The homologous mouse gene is termed Tca-3.

Discovery

CCL is the first human CCL chemokine that was identified by molecular cloning during searching for genes expressed by T cells.

Function

CCL1 is a small glycoprotein with a molecular weight of approximately 15-16 kDa. CCL1 is secreted by activated monocytes/macrophages, T lymphocytes and endothelial cells. CCL1 binds to the chemokine receptor CCR8 and induces Ca2+ influx, chemotaxis and regulate apoptosis. CCR8 is constitutively expressed in monocytes/macrophages, Th2, and regulatory T lymphocytes. Thus, CCL1 mainly acts as a chemoattractant for monocytes/macrophages, T lymphocytes, specially Th2-differentiated T cells and a subset of T regulatory cells in vitro into inflammatory site. It can also attract NK cells, immature B cells but does not attract neutrophils.

CCL1 stimulates a transient increase in the concentration of cytoplasmic free calcium in monocytes but not in other type of cells. Furthermore, CCL1 inhibits apoptosis in thymic cell lines by the RAS/MAPK pathway but can prevent dexamethasone-induced apoptosis in cultured murine thymic lymphoma cells.

Clinical importance

CCL1 is involved in inflammatory processes through leukocyte recruitment and could play a crucial role in angiogenesis and other viral and tumoral processes. For example, CCL1 transcription was increased in primary human CD4 T cells expressing T cell immunoglobulin and protein 3 containing the mucin domain (TIM-3) and was identified as a differentially transcribed gene in CD4 cells T cells expressing TIM-3 that play a role in the regulation anti-tumor immunity. CCL1 is also overexpressed in ATL cells and mediates an autocrine antiapoptotic loop along CCR8 for in vivo growth and survival of leukemic cells. Due to these facts, the dysregulation of CCL1 can leads in pathogenesis of several diseases. Some single nucleotide polymorphisms (SNPs) in the CCL1 gene are associated with exacerbations of chronic obstructive pulmonary disease (COPD).

CCL1 plays a role in various CNS functions and could be associated with some neuroinflammatory disorders. In addition to other chemokines, such as CCL2, CCL3, and CCL4, the presence of CCL1 has been reported in the development of brain abscesses, most likely leading to an influx of lymphocytes and monocytes and thus to an adaptive immune response.

Because CCL1 binds to the CCR8 receptor, some diseases can be caused by dysregulation and dysfunction of this receptor. For example, CCL1 and CCR8 mRNA expression has been detected in the CNS of mice with experimental autoimmune encephalomyelitis (EAE). However, the CCR8 receptor has also been shown to be associated with phagocytic macrophages and activated microglia in MS lesions and directly correlate with demyelinating activity. The CCR8 receptor can serve as a basic receptor for various strains of HIV-1 tropical, dual-tropical and macrophage tropics of HIV-1. Thus, CCl1 has also been studied as a possible potent inhibitor of fusion of cells and cells mediated by HIV-1 envelope and viral infection.

Due to the pathologies that can be caused by dysregulation of the CCR8 receptor, some research are focused on the possibilities of inhibiting this receptor. To suppress the apoptotic activity of CCL1, removing three amino acids from the C-terminus of CCL1 reduces CCR8 binding but converts CCL1 to a more potent CCR8 agonist, leading to increased intracellular calcium release and increased antiapoptotic activity.

References

1. ^ Rollins BJ (August 1997). "Chemokines". Blood. 90 (3): 909–28. doi:10.1182/blood.V90.3.909. PMID 9242519.
2. ^ Miller MD, Krangel MS (April 1992). "The human cytokine I-309 is a monocyte chemoattractant". Proceedings of the National Academy of Sciences of the United States of America. 89 (7): 2950–4. Bibcode:1992PNAS...89.2950M. doi:10.1073/pnas.89.7.2950. PMC 48781. PMID 1557400.
3. Miller MD, Wilson SD, Dorf ME, Seuanez HN, O'Brien SJ, Krangel MS (October 1990). "Sequence and chromosomal location of the I-309 gene. Relationship to genes encoding a family of inflammatory cytokines". Journal of Immunology. 145 (8): 2737–44. doi:10.4049/jimmunol.145.8.2737. PMID 2212659.
4. Wilson SD, Burd PR, Billings PR, Martin CA, Dorf ME (September 1988). "The expression and regulation of a potential lymphokine gene (TCA3) in CD4 and CD8 T cell clones". Journal of Immunology. 141 (5): 1563–70. doi:10.4049/jimmunol.141.5.1563. PMID 2457620.
5. ^ Tiffany HL, Lautens LL, Gao JL, Pease J, Locati M, Combadiere C, et al. (July 1997). "Identification of CCR8: a human monocyte and thymus receptor for the CC chemokine I-309". The Journal of Experimental Medicine. 186 (1): 165–70. doi:10.1084/jem.186.1.165. PMC 2198957. PMID 9207005.
6. ^ Trebst C, Staugaitis SM, Kivisäkk P, Mahad D, Cathcart MK, Tucky B, et al. (February 2003). "CC chemokine receptor 8 in the central nervous system is associated with phagocytic macrophages". The American Journal of Pathology. 162 (2): 427–38. doi:10.1016/S0002-9440(10)63837-0. PMC 1851139. PMID 12547701.
7. Zingoni A, Soto H, Hedrick JA, Stoppacciaro A, Storlazzi CT, Sinigaglia F, et al. (July 1998). "The chemokine receptor CCR8 is preferentially expressed in Th2 but not Th1 cells". Journal of Immunology. 161 (2): 547–51. doi:10.4049/jimmunol.161.2.547. PMID 9670926.
8. Louahed J, Struyf S, Demoulin JB, Parmentier M, Van Snick J, Van Damme J, Renauld JC (February 2003). "CCR8-dependent activation of the RAS/MAPK pathway mediates anti-apoptotic activity of I-309/ CCL1 and vMIP-I". European Journal of Immunology. 33 (2): 494–501. doi:10.1002/immu.200310025. PMID 12645948.
9. Van Snick J, Houssiau F, Proost P, Van Damme J, Renauld JC (September 1996). "I-309/T cell activation gene-3 chemokine protects murine T cell lymphomas against dexamethasone-induced apoptosis". Journal of Immunology. 157 (6): 2570–6. doi:10.4049/jimmunol.157.6.2570. PMID 8805659.
10. Tamgüney G, Van Snick J, Fickenscher H (November 2004). "Autocrine stimulation of rhadinovirus-transformed T cells by the chemokine CCL1/I-309". Oncogene. 23 (52): 8475–85. doi:10.1038/sj.onc.1207903. PMID 15378023.
11. ^ Ruckes T, Saul D, Van Snick J, Hermine O, Grassmann R (August 2001). "Autocrine antiapoptotic stimulation of cultured adult T-cell leukemia cells by overexpression of the chemokine I-309". Blood. 98 (4): 1150–9. doi:10.1182/blood.v98.4.1150. PMID 11493464.
12. Bernardini G, Spinetti G, Ribatti D, Camarda G, Morbidelli L, Ziche M, et al. (December 2000). "I-309 binds to and activates endothelial cell functions and acts as an angiogenic molecule in vivo". Blood. 96 (13): 4039–45. doi:10.1182/blood.V96.13.4039. PMID 11110671.
13. Takabatake N, Shibata Y, Abe S, Wada T, Machiya J, Igarashi A, et al. (October 2006). "A single nucleotide polymorphism in the CCL1 gene predicts acute exacerbations in chronic obstructive pulmonary disease". American Journal of Respiratory and Critical Care Medicine. 174 (8): 875–85. doi:10.1164/rccm.200603-443OC. PMID 16864713.
14. Kielian T, Barry B, Hickey WF (April 2001). "CXC chemokine receptor-2 ligands are required for neutrophil-mediated host defense in experimental brain abscesses". Journal of Immunology. 166 (7): 4634–43. doi:10.4049/jimmunol.166.7.4634. PMID 11254722.
15. Godiska R, Chantry D, Dietsch GN, Gray PW (May 1995). "Chemokine expression in murine experimental allergic encephalomyelitis". Journal of Neuroimmunology. 58 (2): 167–76. doi:10.1016/0165-5728(95)00008-p. PMID 7539012. S2CID 13148735.
16. Horuk R, Hesselgesser J, Zhou Y, Faulds D, Halks-Miller M, Harvey S, et al. (January 1998). "The CC chemokine I-309 inhibits CCR8-dependent infection by diverse HIV-1 strains". The Journal of Biological Chemistry. 273 (1): 386–91. doi:10.1074/jbc.273.1.386. PMID 9417093.
17. Denis C, Deiteren K, Mortier A, Tounsi A, Fransen E, Proost P, et al. (2012). "C-terminal clipping of chemokine CCL1/I-309 enhances CCR8-mediated intracellular calcium release and anti-apoptotic activity". PLOS ONE. 7 (3): e34199. Bibcode:2012PLoSO...734199D. doi:10.1371/journal.pone.0034199. PMC 3313992. PMID 22479563.

• Genes on human chromosome 17
• Cytokines