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]
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. [4]
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. [5]
CCL7 was first characterized from osteosarcoma supernatant. [6] 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. [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]
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. [5] [7] [13]
CCL7 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 leukocytes to infected tissues to mediate the immune response. [12] Furthermore, CCL7 has an 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 inflammation. [16] 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. [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 3–5 days after the stimulation. [18]
CCL7 has been shown to interact with MMP2 by binding CCR2 receptor. [19]
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). [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 increased 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, an 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]
Chemokines, or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers.
Interleukin 8 is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage vesicles, the Weibel–Palade bodies. In humans, the interleukin-8 protein is encoded by the CXCL8 gene. IL-8 is initially produced as a precursor peptide of 99 amino acids which then undergoes cleavage to create several active IL-8 isoforms. In culture, a 72 amino acid peptide is the major form secreted by macrophages.
The chemokine ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. CCL2 is a small cytokine that belongs to the CC chemokine family. CCL2 tightly regulates cellular mechanics and thereby recruits monocytes, memory T cells, and dendritic cells to the sites of inflammation produced by either tissue injury or infection.
Chemokine ligands 4 previously known as macrophage inflammatory protein (MIP-1β), is a protein which in humans is encoded by the CCL4 gene. CCL4 belongs to a cluster of genes located on 17q11-q21 of the chromosomal region. Identification and localization of the gene on the chromosome 17 was in 1990 although the discovery of MIP-1 was initiated in 1988 with the purification of a protein doublet corresponding to inflammatory activity from supernatant of endotoxin-stimulated murine macrophages. At that time, it was also named as "macrophage inflammatory protein-1" (MIP-1) due to its inflammatory properties.
Chemokine 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.
Chemokine ligand 8 (CCL8), also known as monocyte chemoattractant protein 2 (MCP2), is a protein that in humans is encoded by the CCL8 gene.
The eotaxins are a CC chemokine subfamily of eosinophil chemotactic proteins. Eotaxin is a special CC chemokine because it primarily attracts eosinophils. By being a chemoattractant for eosinophils, eotaxin has a direct relationship with inflammation. This is because eosinophils are known to promote inflammation. In order to induce stimulation, eotaxin binds with the CCR-3 receptor. The binding of eotaxin with the CCR-3 Receptor recruits eosinophils, which ultimately induces inflammation. According to early studies, the production of eotaxin can be linked to Th2 lymphocytes. Eotaxin appears to be T-cell dependent because of evidence that suggests that eosinophil recruitment is regulated by Th2 lymphocytes. The regulation occurs because of the presence of the CCR-3 Receptor on the Th2 lymphocyte. Some examples of the types of cells that have the ability of synthesizing eotaxin are lung cells, vascular endothelial cells, and macrophages.
Chemokine ligand 20 (CCL20) or liver activation regulated chemokine (LARC) or Macrophage Inflammatory Protein-3 (MIP3A) is a small cytokine belonging to the CC chemokine family. It is strongly chemotactic for lymphocytes and weakly attracts neutrophils. CCL20 is implicated in the formation and function of mucosal lymphoid tissues via chemoattraction of lymphocytes and dendritic cells towards the epithelial cells surrounding these tissues. CCL20 elicits its effects on its target cells by binding and activating the chemokine receptor CCR6.
Chemokine ligand 15 (CCL15) is a small cytokine belonging to the CC chemokine family that is also known as leukotactin-1, MIP5 and HCC-2. CCL15 is expressed in liver, small intestine, colon, and in certain leukocytes and macrophages of the lung. It is chemotactic for neutrophils, monocytes, and lymphocytes and elicits its effects by binding to cell surface chemokine receptors like CCR1 and CCR3. The human CCL15 gene spans four exons and is located in a head-to-tail orientation on chromosome 17 with the gene of another CC chemokine known as CCL14.
C-C motif chemokine 22 is a protein that in humans is encoded by the CCL22 gene.
Chemokine ligand 9 (CXCL9) is a small cytokine belonging to the CXC chemokine family that is also known as monokine induced by gamma interferon (MIG). The CXCL9 is one of the chemokine which plays role to induce chemotaxis, promote differentiation and multiplication of leukocytes, and cause tissue extravasation.
C-X-C motif chemokine 11 (CXCL11) is a protein that in humans is encoded by the CXCL11 gene.
The chemokine ligand 1 (CXCL1) is a small peptide belonging to the CXC chemokine family that acts as a chemoattractant for several immune cells, especially neutrophils or other non-hematopoietic cells to the site of injury or infection and plays an important role in regulation of immune and inflammatory responses. It was previously called GRO1 oncogene, GROα, neutrophil-activating protein 3 (NAP-3) and melanoma growth stimulating activity, alpha (MGSA-α). CXCL1 was first cloned from a cDNA library of genes induced by platelet-derived growth factor (PDGF) stimulation of BALB/c-3T3 murine embryonic fibroblasts and named "KC" for its location in the nitrocellulose colony hybridization assay. This designation is sometimes erroneously believed to be an acronym and defined as "keratinocytes-derived chemokine". Rat CXCL1 was first reported when NRK-52E cells were stimulated with interleukin-1β (IL-1β) and lipopolysaccharide (LPS) to generate a cytokine that was chemotactic for rat neutrophils, cytokine-induced neutrophil chemoattractant (CINC). In humans, this protein is encoded by the gene CXCL1 and is located on human chromosome 4 among genes for other CXC chemokines.
C-X-C motif chemokine 5 is a protein that in humans is encoded by the CXCL5 gene.
Chemokine ligand 6 (CXCL6) is a small cytokine belonging to the CXC chemokine family that is also known as granulocyte chemotactic protein 2 (GCP-2). As its former name suggests, CXCL6 is a chemoattractant for neutrophilic granulocytes. It elicits its chemotactic effects by interacting with the chemokine receptors CXCR1 and CXCR2. The gene for CXCL6 is located on human chromosome 4 in a cluster with other CXC chemokine genes.
Chemokine ligand 12 (CCL12) is a small cytokine belonging to the CC chemokine family that has been described in mice. It is also known as monocyte chemotactic protein 5 (MCP-5) and, due to its similarity with the human chemokine MCP-1, sometimes it is called MCP-1-related chemokine. CCL12 specifically attracts eosinophils, monocytes and lymphocytes. This chemokine is found predominantly in lymph nodes and thymus under normal conditions, and its expression can be hugely induced in macrophages. It is thought to coordinate cell movements during early allergic reactions, and immune response to pathogens. The gene for CCL12 is found in a cluster of CC chemokines on mouse chromosome 11.
C-C chemokine receptor type 2 (CCR2 or CD192 is a protein that in humans is encoded by the CCR2 gene. CCR2 is a CC chemokine receptor.
C-C chemokine receptor type 1 is a protein that in humans is encoded by the CCR1 gene.
C-C chemokine receptor type 3 is a protein that in humans is encoded by the CCR3 gene.
Chemokine ligand 3-like 1, also known as CCL3L1, is a protein which in humans is encoded by the CCL3L1 gene.
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