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).{{cite journal | vauthors = Rollins BJ | title = Chemokines | journal = Blood | volume = 90 | issue = 3 | pages = 909–28 | date = August 1997 | doi = 10.1182/blood.V90.3.909 | pmid = 9242519 | doi-access = free }}

Genomics

In the human genome, CCL7 is encoded by the CCL7 gene which is one of the several chemokine genes clustered on chromosome 17q11.2-q12. This region contains the gene for the MCP subset of CC chemokines. The CCL7 gene has been given the locus symbol SCYA7.{{cite journal | vauthors = Opdenakker G, Fiten P, Nys G, Froyen G, Van Roy N, Speleman F, Laureys G, Van Damme J | display-authors = 6 | title = The human MCP-3 gene (SCYA7): cloning, sequence analysis, and assignment to the C-C chemokine gene cluster on chromosome 17q11.2-q12 | journal = Genomics | volume = 21 | issue = 2 | pages = 403–8 | date = May 1994 | pmid = 7916328 | doi = 10.1006/geno.1994.1283 }}

The gene consists of three exons and two introns. The first exon contains a 5′-untranslated region (5′-UTR), the information for the signal sequence (23 amino acids), and the mature protein's first two amino acids. 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.{{cite journal | vauthors = Van Coillie E, Van Damme J, Opdenakker G | title = The MCP/eotaxin subfamily of CC chemokines | journal = Cytokine & Growth Factor Reviews | volume = 10 | issue = 1 | pages = 61–86 | date = March 1999 | pmid = 10379912 | doi = 10.1016/s1359-6101(99)00005-2 }}

Molecular biology

CCL7 was first characterized from osteosarcoma supernatant.{{cite journal | vauthors = Van Damme J, Proost P, Lenaerts JP, Opdenakker G | title = Structural and functional identification of two human, tumor-derived monocyte chemotactic proteins (MCP-2 and MCP-3) belonging to the chemokine family | journal = The Journal of Experimental Medicine | volume = 176 | issue = 1 | pages = 59–65 | date = July 1992 | pmid = 1613466 | pmc = 2119277 | doi = 10.1084/jem.176.1.59 }} CCL7 consists 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.{{cite journal | vauthors = Liu Y, Cai Y, Liu L, Wu Y, Xiong X | title = Crucial biological functions of CCL7 in cancer | journal = PeerJ | volume = 6 | pages = e4928 | date = 2018 | pmid = 29915688 | pmc = 6004300 | doi = 10.7717/peerj.4928 | doi-access = free }} In contrast to most chemokines, CCL7 exists in a general monomeric form, differing from the dimer formed in a highly concentrated solution.{{cite journal | vauthors = Kim KS, Rajarathnam K, Clark-Lewis I, Sykes BD | title = Structural characterization of a monomeric chemokine: monocyte chemoattractant protein-3 | journal = FEBS Letters | volume = 395 | issue = 2–3 | pages = 277–82 | date = October 1996 | pmid = 8898111 | doi = 10.1016/0014-5793(96)01024-1 | s2cid = 24062093 | doi-access = free | bibcode = 1996FEBSL.395..277K }}{{cite journal | vauthors = Meunier S, Bernassau JM, Guillemot JC, Ferrara P, Darbon H | title = Determination of the three-dimensional structure of CC chemokine monocyte chemoattractant protein 3 by 1H two-dimensional NMR spectroscopy | journal = Biochemistry | volume = 36 | issue = 15 | pages = 4412–22 | date = April 1997 | pmid = 9109648 | doi = 10.1021/bi9627929 }}

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

CCL7 mediates effects on the immune cell types through binding to numerous receptors, including CCR1, CCR2, CCR3, CCR5, and CCR10.{{cite journal | vauthors = Palomino DC, Marti LC | title = Chemokines and immunity | journal = Einstein | volume = 13 | issue = 3 | pages = 469–73 | date = July 2015 | pmid = 26466066 | pmc = 4943798 | doi = 10.1590/S1679-45082015RB3438 }} These receptors belongs to the G protein-coupled seven-transmembrane receptors.{{cite journal | vauthors = Griffith JW, Sokol CL, Luster AD | title = Chemokines and chemokine receptors: positioning cells for host defense and immunity | journal = Annual Review of Immunology | volume = 32 | pages = 659–702 | date = 2014 | pmid = 24655300 | doi = 10.1146/annurev-immunol-032713-120145 | s2cid = 10579265 | doi-access = free }} CCL7 can also interact with cell surface glycosaminoglycans (GAGs) present on all animal cell surfaces.{{cite journal | vauthors = Menten P, Wuyts A, Van Damme J | title = Monocyte chemotactic protein-3 | journal = European Cytokine Network | volume = 12 | issue = 4 | pages = 554–60 | date = October 2001 | pmid = 11781181 }}

Function

CCL7 is expressed in many types of cells, including stromal cells, keratinocytes, airway smooth muscle cells, parenchymal cells, fibroblasts and leukocytes and also in tumor cells.{{cite journal | vauthors = Menten P, Proost P, Struyf S, Van Coillie E, Put W, Lenaerts JP, Conings R, Jaspar JM, De Groote D, Billiau A, Opdenakker G, Van Damme J | display-authors = 6 | title = Differential induction of monocyte chemotactic protein-3 in mononuclear leukocytes and fibroblasts by interferon-alpha/beta and interferon-gamma reveals MCP-3 heterogeneity | journal = European Journal of Immunology | volume = 29 | issue = 2 | pages = 678–85 | date = February 1999 | pmid = 10064085 | doi = 10.1002/(SICI)1521-4141(199902)29:02<678::AID-IMMU678>3.0.CO;2-J | doi-access = free }}

CCL7 mainly acts as a chemoattractant for several leukocytes, including monocytes, eosinophils, basophils, dendritic cells (DCs), neutrophils, NK cells and activated T lymphocytes.{{cite journal | vauthors = Ali S, Robertson H, Wain JH, Isaacs JD, Malik G, Kirby JA | title = A non-glycosaminoglycan-binding variant of CC chemokine ligand 7 (monocyte chemoattractant protein-3) antagonizes chemokine-mediated inflammation | journal = Journal of Immunology | volume = 175 | issue = 2 | pages = 1257–66 | date = July 2005 | pmid = 16002730 | doi = 10.4049/jimmunol.175.2.1257 | s2cid = 32126355 | doi-access = free }} Thus, chemotactic factor CCL7 recruits leukocytes to infected tissues to mediate the immune response. Furthermore, CCL7 has an influence to diapedesis and extravasation of leukocytes.{{cite journal | vauthors = Weber KS, von Hundelshausen P, Clark-Lewis I, Weber PC, Weber C | title = Differential immobilization and hierarchical involvement of chemokines in monocyte arrest and transmigration on inflamed endothelium in shear flow | journal = European Journal of Immunology | volume = 29 | issue = 2 | pages = 700–12 | date = February 1999 | pmid = 10064088 | doi = 10.1002/(SICI)1521-4141(199902)29:02<700::AID-IMMU700>3.0.CO;2-1 | s2cid = 25639109 }} 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 inflammation.{{cite journal | vauthors = Tsou CL, Peters W, Si Y, Slaymaker S, Aslanian AM, Weisberg SP, Mack M, Charo IF | display-authors = 6 | title = Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites | journal = The Journal of Clinical Investigation | volume = 117 | issue = 4 | pages = 902–9 | date = April 2007 | pmid = 17364026 | pmc = 1810572 | doi = 10.1172/JCI29919 }} It was also reported, that CCL7 can also induce neutrophil migration to the inflammatory site by increasing intracellular Ca2+ flux, which is more typical for the CXC chemokine family members.{{cite journal | vauthors = Fioretti F, Fradelizi D, Stoppacciaro A, Ramponi S, Ruco L, Minty A, Sozzani S, Garlanda C, Vecchi A, Mantovani A | display-authors = 6 | title = 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 = Journal of Immunology | volume = 161 | issue = 1 | pages = 342–6 | date = July 1998 | doi = 10.4049/jimmunol.161.1.342 | pmid = 9647242 | s2cid = 36845889 | doi-access = free }}

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 3–5 days after the stimulation.{{cite journal | vauthors = Song A, Nikolcheva T, Krensky AM | title = Transcriptional regulation of RANTES expression in T lymphocytes | journal = Immunological Reviews | volume = 177 | pages = 236–45 | date = October 2000 | pmid = 11138780 | doi = 10.1034/j.1600-065x.2000.17610.x | s2cid = 30184294 }}

CCL7 has been shown to interact with MMP2 by binding CCR2 receptor.{{cite journal | vauthors = Opdenakker G, Froyen G, Fiten P, Proost P, Van Damme J | title = Human monocyte chemotactic protein-3 (MCP-3): molecular cloning of the cDNA and comparison with other chemokines | journal = Biochemical and Biophysical Research Communications | volume = 191 | issue = 2 | pages = 535–42 | date = March 1993 | pmid = 8461011 | doi = 10.1006/bbrc.1993.1251 }}

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 participating in the elimination of Listeria monocytogenes infections by the recruitment of monocytes and TNF/iNOS-producing dendritic cells (TipDCs).{{cite book | vauthors = Serbina NV, Shi C, Pamer EG | title = Immunity to Listeria Monocytogenes | chapter = Monocyte-mediated immune defense against murine Listeria monocytogenes infection | series = Advances in Immunology | volume = 113 | pages = 119–34 | date = 2012 | pmid = 22244581 | pmc = 3985089 | doi = 10.1016/B978-0-12-394590-7.00003-8 | isbn = 9780123945907 }} Next, the role of the CCL7 was also observed in the mouse infected by West Nile Virus. The genetically deficient mice in CCL7 have increased mortality because of decrease in monocytes and neutrophils.{{cite journal | vauthors = Bardina SV, Michlmayr D, Hoffman KW, Obara CJ, Sum J, Charo IF, Lu W, Pletnev AG, Lim JK | display-authors = 6 | title = Differential Roles of Chemokines CCL2 and CCL7 in Monocytosis and Leukocyte Migration during West Nile Virus Infection | journal = Journal of Immunology | volume = 195 | issue = 9 | pages = 4306–18 | date = November 2015 | pmid = 26401006 | pmc = 4610864 | doi = 10.4049/jimmunol.1500352 }} Early induction of CCL7 downstream of TLR9 signaling also promotes the development of robust immunity to cryptococcal infections.{{cite journal | vauthors = Ouchi N, Parker JL, Lugus JJ, Walsh K | title = Adipokines in inflammation and metabolic disease | journal = Nature Reviews. Immunology | volume = 11 | issue = 2 | pages = 85–97 | date = February 2011 | pmid = 21252989 | pmc = 3518031 | doi = 10.1038/nri2921 }}

Diseases associated with CCL7 dysregulation are observed. For example, an abnormal increase of CCL7 worsens many disorders, like HIV or lesional psoriasis.{{cite journal | vauthors = Atluri VS, Pilakka-Kanthikeel S, Garcia G, Jayant RD, Sagar V, Samikkannu T, Yndart A, Nair M | display-authors = 6 | title = Effect of Cocaine on HIV Infection and Inflammasome Gene Expression Profile in HIV Infected Macrophages | journal = Scientific Reports | volume = 6 | pages = 27864 | date = June 2016 | pmid = 27321752 | pmc = 4913267 | doi = 10.1038/srep27864 | bibcode = 2016NatSR...627864A }}{{cite journal | vauthors = Brunner PM, Glitzner E, Reininger B, Klein I, Stary G, Mildner M, Uhrin P, Sibilia M, Stingl G | display-authors = 6 | title = CCL7 contributes to the TNF-alpha-dependent inflammation of lesional psoriatic skin | journal = Experimental Dermatology | volume = 24 | issue = 7 | pages = 522–8 | date = July 2015 | pmid = 25828150 | doi = 10.1111/exd.12709 | s2cid = 2805402 }} Furthermore, CCL7 is implicated in various immunological diseases, as ulcerative colitis, multiple sclerosis or nonatopic and atopic asthma.{{cite journal | vauthors = Romagnani S | title = Cytokines and chemoattractants in allergic inflammation | journal = Molecular Immunology | volume = 38 | issue = 12–13 | pages = 881–5 | date = May 2002 | pmid = 12009564 | doi = 10.1016/s0161-5890(02)00013-5 }}

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

References

External links

{{UCSC gene info|CCL7}}

Category:Signal transduction

Category:Cytokines