CCL7

Chemokine (C-C motif) ligand 7 (CCL7) is a small cytokine that was previously called monocyte-chemotactic protein 3 (MCP3). CCL7 is a small protein that belongs to the CC chemokine family and is most closely related to CCL2 (previously called MCP1).[3]

CCL7
Available structures
PDBHuman UniProt search: PDBe RCSB
Identifiers
AliasesCCL7, FIC, MARC, MCP-3, MCP3, NC28, SCYA6, SCYA7, C-C motif chemokine ligand 7
External IDsOMIM: 158106 HomoloGene: 4568 GeneCards: CCL7
Gene location (Human)
Chr.Chromosome 17 (human)[1]
Band17q12Start34,270,221 bp[1]
End34,272,242 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

6354

n/a

Ensembl

ENSG00000108688

n/a

UniProt

P80098

n/a

RefSeq (mRNA)

NM_006273

n/a

RefSeq (protein)

NP_006264

n/a

Location (UCSC)Chr 17: 34.27 – 34.27 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

Genomics

In the human genome, CCL7 is encoded by CCL7 gene which is one of the several chemokine genes clustered on the chromosome 17q11.2-q12. This region contain the gene for the MCP subset of CC chemokines. The CCL7 gene has been given the locus symbol SCYA7.[4]

The gene is consist of three exons and two introns. The first exon contains a 5′-untranslated region (5′-UTR), and the information for the signal sequence (23 amino acids), and the first two amino acids of the mature protein. The second exon encodes amino acids 3–42 of the mature proteins. The third exon is composed of the C-terminal region of the protein, a 3′-UTR containing one or more destabilizing AU-rich sequences and a polyadenylation signal.[5]

Molecular biology

CCL7 was first characterized from osteosarcoma supernatant.[6] CCL7 is consist of 99 amino acids, which contains 23-amino acid signal peptide. The mature protein about 76 amino acids is secreted after cleavage of the signal peptide.[7] In contrast to most chemokines, CCL7 exists in a general monomeric form, differing from the dimer formed in a highly concentrated solution.[8][9]

CCL7 can exist in four different glycotypes with a molecular weight 11, 13, 17 and 18 kDa in COS cells. [5]

CCL7 mediates effects on the immune cell types through binding to numerous receptors including CCR1, CCR2, CCR3, CCR5, and CCR10.[10][7] These receptors belongs to the G protein-coupled seven-transmembrane receptors.[11] CCL7 can also interact with cell surface glycosaminoglycans (GAGs) present on all animal cell surfaces.[12]

Function

CCL7 is expressed in many types of cells including stromal cells, keratinocytes, airway smooth muscle cells, parenchymal cells, fibroblasts and leukocytes but also in tumor cells.[5][7][13]

CC7 mainly acts as a chemoattractant for several leukocytes, including monocytes, eosinophils, basophils, dendritic cells (DCs), neutrophils, NK cells and activated T lymphocytes.[12][14] Thus, chemotactic factor CCL7 recruits a leukocytes to infected tissues to mediate the immune response.[12] Furthermore, CCL7 has influence to diapedesis and extravasation of leukocytes.[15] The positive effect of CCL7 is mainly observed in monocyte mobilization from bone marrow to blood circulation and in the recruitment of monocytes to sites of inlammation.[16] It was also reported, that CCL7 can also induce neutrophil migration to inflammatory site by increasing intracellular Ca2+ flux, which is more typical for the members of the CXC chemokine family.[17]

The speed of immune responses varies depending on the type of the cells. In epithelial cells, fibroblasts and endothelial cells the response is immediate after the stimulation by proinflammatory cytokines as IL-1β and TNFα. In T lymphocytes the expression of CCL7 occurs after the 3-5 days after the stimulation.[18]

CCL7 has been shown to interact with MMP2 by binding CCR2 receptor.[19]

Clinical importance

CCL7 is a multipotent chemokine involved in anti-bacterial, anti-viral and anti-fungal immune responses. For example, CCL7-mediated stimulation of CCR2 chemokine receptors on monocytes is participate in the elimination of Listeria monocytogenes infections by the recruitment of monocytes and TNF/iNOS-producing dendritic cells (TipDCs).[20] Next, the role of the CCL7 was also observed in the mouse infected by West Nile Virus. The genetically deficient mice in CCL7 have inreased mortality because of decrease in monocytes and neutrophils.[21] Early induction of CCL7 downstream of TLR9 signaling also promotes the development of robust immunity to cryptococcal infections.[22]

Diseases associated with CCL7 dysregulation are observed. For example, abnormal increase of CCL7 worsens many disorders, like HIV or lesional psoriasis.[23][24] Furthermore, CCL7 is implicated in various immunological diseases, as ulcerative colitis, multiple sclerosis or nonatopic and atopic asthma.[12][25]

It seems, that the expression of CCL7 can activate an antitumor immune response.[17]

References
  1. GRCh38: Ensembl release 89: ENSG00000108688 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. Rollins BJ (August 1997). "Chemokines". Blood. 90 (3): 909–28. PMID 9242519.
  4. Opdenakker G, Fiten P, Nys G, Froyen G, Van Roy N, Speleman F, et al. (May 1994). "The human MCP-3 gene (SCYA7): cloning, sequence analysis, and assignment to the C-C chemokine gene cluster on chromosome 17q11.2-q12". Genomics. 21 (2): 403–8. doi:10.1006/geno.1994.1283. PMID 7916328.
  5. Van Coillie E, Van Damme J, Opdenakker G (March 1999). "The MCP/eotaxin subfamily of CC chemokines". Cytokine & Growth Factor Reviews. 10 (1): 61–86. doi:10.1016/s1359-6101(99)00005-2. PMID 10379912.
  6. Van Damme J, Proost P, Lenaerts JP, Opdenakker G (July 1992). "Structural and functional identification of two human, tumor-derived monocyte chemotactic proteins (MCP-2 and MCP-3) belonging to the chemokine family". The Journal of Experimental Medicine. 176 (1): 59–65. doi:10.1084/jem.176.1.59. PMC 2119277. PMID 1613466.
  7. Liu Y, Cai Y, Liu L, Wu Y, Xiong X (2018). "Crucial biological functions of CCL7 in cancer". PeerJ. 6: e4928. doi:10.7717/peerj.4928. PMC 6004300. PMID 29915688.
  8. Kim KS, Rajarathnam K, Clark-Lewis I, Sykes BD (October 1996). "Structural characterization of a monomeric chemokine: monocyte chemoattractant protein-3". FEBS Letters. 395 (2–3): 277–82. doi:10.1016/0014-5793(96)01024-1. PMID 8898111.
  9. Meunier S, Bernassau JM, Guillemot JC, Ferrara P, Darbon H (April 1997). "Determination of the three-dimensional structure of CC chemokine monocyte chemoattractant protein 3 by 1H two-dimensional NMR spectroscopy". Biochemistry. 36 (15): 4412–22. doi:10.1021/bi9627929. PMID 9109648.
  10. Palomino DC, Marti LC (July 2015). "Chemokines and immunity". Einstein. 13 (3): 469–73. doi:10.1590/S1679-45082015RB3438. PMC 4943798. PMID 26466066.
  11. Griffith JW, Sokol CL, Luster AD (2014). "Chemokines and chemokine receptors: positioning cells for host defense and immunity". Annual Review of Immunology. 32: 659–702. doi:10.1146/annurev-immunol-032713-120145. PMID 24655300.
  12. Menten P, Wuyts A, Van Damme J (October 2001). "Monocyte chemotactic protein-3". European Cytokine Network. 12 (4): 554–60. PMID 11781181.
  13. Menten P, Proost P, Struyf S, Van Coillie E, Put W, Lenaerts JP, et al. (February 1999). "Differential induction of monocyte chemotactic protein-3 in mononuclear leukocytes and fibroblasts by interferon-alpha/beta and interferon-gamma reveals MCP-3 heterogeneity". European Journal of Immunology. 29 (2): 678–85. doi:10.1002/(SICI)1521-4141(199902)29:023.0.CO;2-J. PMID 10064085.
  14. Ali S, Robertson H, Wain JH, Isaacs JD, Malik G, Kirby JA (July 2005). "A non-glycosaminoglycan-binding variant of CC chemokine ligand 7 (monocyte chemoattractant protein-3) antagonizes chemokine-mediated inflammation". Journal of Immunology. 175 (2): 1257–66. doi:10.4049/jimmunol.175.2.1257. PMID 16002730.
  15. Weber KS, von Hundelshausen P, Clark-Lewis I, Weber PC, Weber C (February 1999). "Differential immobilization and hierarchical involvement of chemokines in monocyte arrest and transmigration on inflamed endothelium in shear flow". European Journal of Immunology. 29 (2): 700–12. doi:10.1002/(SICI)1521-4141(199902)29:023.0.CO;2-1. PMID 10064088.
  16. Tsou CL, Peters W, Si Y, Slaymaker S, Aslanian AM, Weisberg SP, et al. (April 2007). "Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites". The Journal of Clinical Investigation. 117 (4): 902–9. doi:10.1172/JCI29919. PMC 1810572. PMID 17364026.
  17. Fioretti F, Fradelizi D, Stoppacciaro A, Ramponi S, Ruco L, Minty A, et al. (July 1998). "Reduced tumorigenicity and augmented leukocyte infiltration after monocyte chemotactic protein-3 (MCP-3) gene transfer: perivascular accumulation of dendritic cells in peritumoral tissue and neutrophil recruitment within the tumor". Journal of Immunology. 161 (1): 342–6. PMID 9647242.
  18. Song A, Nikolcheva T, Krensky AM (October 2000). "Transcriptional regulation of RANTES expression in T lymphocytes". Immunological Reviews. 177: 236–45. doi:10.1034/j.1600-065x.2000.17610.x. PMID 11138780.
  19. Opdenakker G, Froyen G, Fiten P, Proost P, Van Damme J (March 1993). "Human monocyte chemotactic protein-3 (MCP-3): molecular cloning of the cDNA and comparison with other chemokines". Biochemical and Biophysical Research Communications. 191 (2): 535–42. doi:10.1006/bbrc.1993.1251. PMID 8461011.
  20. Serbina NV, Shi C, Pamer EG (2012). "Monocyte-mediated immune defense against murine Listeria monocytogenes infection". Advances in Immunology. 113: 119–34. doi:10.1016/B978-0-12-394590-7.00003-8. PMC 3985089. PMID 22244581.
  21. Bardina SV, Michlmayr D, Hoffman KW, Obara CJ, Sum J, Charo IF, et al. (November 2015). "Differential Roles of Chemokines CCL2 and CCL7 in Monocytosis and Leukocyte Migration during West Nile Virus Infection". Journal of Immunology. 195 (9): 4306–18. doi:10.4049/jimmunol.1500352. PMC 4610864. PMID 26401006.
  22. Ouchi N, Parker JL, Lugus JJ, Walsh K (February 2011). "Adipokines in inflammation and metabolic disease". Nature Reviews. Immunology. 11 (2): 85–97. doi:10.1038/nri2921. PMC 3518031. PMID 21252989.
  23. Atluri VS, Pilakka-Kanthikeel S, Garcia G, Jayant RD, Sagar V, Samikkannu T, et al. (June 2016). "Effect of Cocaine on HIV Infection and Inflammasome Gene Expression Profile in HIV Infected Macrophages". Scientific Reports. 6: 27864. doi:10.1038/srep27864. PMC 4913267. PMID 27321752.
  24. Brunner PM, Glitzner E, Reininger B, Klein I, Stary G, Mildner M, et al. (July 2015). "CCL7 contributes to the TNF-alpha-dependent inflammation of lesional psoriatic skin". Experimental Dermatology. 24 (7): 522–8. doi:10.1111/exd.12709. PMID 25828150.
  25. Romagnani S (May 2002). "Cytokines and chemoattractants in allergic inflammation". Molecular Immunology. 38 (12–13): 881–5. doi:10.1016/s0161-5890(02)00013-5. PMID 12009564.

Further reading
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