CCL18

Last updated
CCL18
Available structures
PDB Human UniProt search: PDBe RCSB
Identifiers
Aliases CCL18 , chemokine (C-C motif) ligand 18 (pulmonary and activation-regulated), AMAC-1, AMAC1, CKb7, DC-CK1, DCCK1, MIP-4, PARC, SCYA18, C-C motif chemokine ligand 18
External IDs OMIM: 603757 HomoloGene: 48154 GeneCards: CCL18
Orthologs
SpeciesHumanMouse
Entrez

6362

n/a

Ensembl

ENSG00000275385
ENSG00000278167
ENSG00000278006

n/a

UniProt

P55774

n/a

RefSeq (mRNA)

NM_002988

n/a

RefSeq (protein)

NP_002979

n/a

Location (UCSC) Chr 17: 36.06 – 36.07 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

Chemokine (C-C motif) ligand 18 (CCL18) is a small cytokine belonging to the CC chemokine family. The functions of CCL18 have been well studied in laboratory settings, however the physiological effects of the molecule in living organisms have been difficult to characterize because there is no similar protein in rodents that can be studied. The receptor for CCL18 has been identified in humans only recently, which will help scientists understand the molecule's role in the body.

Contents

CCL18 is produced and secreted mainly by innate immune system, and has effects mainly on the adaptive immune system. It was previously known as Pulmonary and activation-regulated chemokine (PARC), dendritic cell (DC)-chemokine 1 (DC-CK1), alternative macrophage activation-associated CC chemokine-1 (AMAC-1), and macrophage inflammatory protein-4 (MIP-4).

Gene and protein structure

The gene of CCL18 is most similar to CCL3. [3] CCL18 is located on chromosome 17, along with many other macrophage inflammatory proteins (MIPs). The gene itself has 3 exons and 2 introns; but, unlike other chemokines, CCL18 includes 2 pseudo-exons (exons that do not appear in the final peptide) in the first intron. [4] Because of these pseudo-exons, it is believed that CCL18 arose as a result of a gene fusion event between CCL3-like protein encoding genes and gained a different function over time due to accumulating mutations. [4] [5] CCL18 is an 89 amino-acid-long protein, with a 20 amino-acid-long peptide signalling sequence (to signal its secretion) at the N’ terminus which is cleaved in the endoplasmic reticulum into a 69 amino-acid-long mature protein. [3]

The gene structure of CCL18 CCL18 Gene Structure.jpg
The gene structure of CCL18

Sources

CCL18 is produced mainly by antigen-presenting cells of the innate immune system. These cells include dendritic cells, monocytes, and macrophages. [7] [8] [9] Neither T-cells nor B-cells are known to produce CCL18. [7] Its production is upregulated in these cells by IL-10, IL-4, and IL-13, which are cytokines that favour a T-helper 2 type response and are generally involved in humoral immunity or for immunosuppression. The presence of IFN-gamma, a T-helper 1 type response cytokine important for cell-mediated immunity, dampens the production of CCL18. [10] Furthermore, CCL18 is induced by fibroblasts, specifically by induction of collagen produced by fibroblasts, which is important in tissue healing and repair. [9] Finally, CCL18 is constitutively and highly expressed in the lungs, suggesting that CCL18 plays role in maintaining homeostasis.

Chemotactic functions

Chemokines are classed as a special type of cytokine that is involved in immune cell trafficking. CCL18 in particular has some chemotactic functions for the innate immune system, but its functions are primarily involved with recruitment of the adaptive immune system. CCL18 is involved in attracting naïve T-cells, [11] T-regulatory cells, [7] [12] T-helper 2 cells, [13] both immunosuppressive and immature Dendritic Cells, [7] [10] basophils, [13] and B-cells (naïve and effector). [6] The T-regulatory cells that CCL18 attracts are not classical T-regulatory cells; these cells do not express FoxP3 as most T-regulatory cells do, and instead non-antigen specifically exert their immunosuppressive functions by secreting IL-10. [9] It is thought that these recruited cells maintain homeostasis under healthy conditions.

Receptor

The classical receptors for chemokines are G-protein coupled receptors (GPCRs), which have 7 transmembrane regions. Following this trend, it was thought that CCL18's receptor is also probably a GPCR. However, for a long time, the physiological receptor has not been found until very recently. To date, are three receptors that have been proposed for CCL18: PITPNM3, GPR30, and CCR8. PITPNM3 is a CCL18 receptor, but PITPNM3 is only expressed on breast cancer cells and not on T-cells nor B-cells, and PITPNM3-CCL8 binding induces Pyk2 and Src mediated signaling, a cancer related signaling pathway, and subsequent metastasis of breast cancer. [14] [15] GPR30 is also reported to bind to CCL18, but binding of CCL18 does not induce chemotaxis; instead, binding of CCL18 to GPR30 blocks both activation of GPR30 by its natural ligands and reduces the ability of CXCL12-dependent activation of acute lymphocytic leukemia B cells. [16] CCR8 is the most recently discovered receptor for CCL18, and the effects of CCR8-CCL18 interactions appear to be physiological, as CCL18 binding to CCR8 induces chemotaxis of Th2 cells. [17] Furthermore, CCL18 binding is competitive with CCR8's previously described ligand, CCL1, further suggesting that CCL18 binds physiologically with CCR8. [17] ) Further elucidation of the role of CCR8 in CCL18-mediated pathologies would allow for better understanding of CCL18's function in these diseases.

Effector functions

CCL18 has a plethora of functions that have been characterized in vitro and in vivo. Strangely, CCL18 seems to play a part in both activation of the immune system and the induction of tolerance and homeostasis at steady-state conditions.


Immune activation

The production of CCL18 is induced by T-helper 2 type cytokines, namely IL-4 and IL-13. Coupled with the fact that CCL18 is highly expressed in patients with allergic asthma [18] and other hypersensitivity diseases, [6] CCL18 seems to play an important role for generating and maintaining a T-helper 2 (Th2) type response. Furthermore, the addition of CCL18 as an adjuvant for a malaria vaccine have shown efficacy, perhaps by recruiting immune cells to the site of vaccination. [19] Finally, CCL18 is expressed by dendritic cells in the germinal center of inflamed lymph nodes, and recruits naïve B-cells for antigen presentation. [20] Perhaps aberrant CCL18 expression is involved in the generation of chronic Th2 response, leading to asthma or arthritis.

Immunosuppression

In addition to immune-activating effects, CCL18 also has strong immunosuppressive effects. CCL18 induces immature dendritic cells to differentiate into an immunosuppressive dendritic cell that is capable producing CCL18 which attract T-cells, suppressing effector T-cell function, and generating T-regulatory cells by secreting large amounts of IL-10. [10] [21] Furthermore, exposure to CCL18 by macrophages causes them to mature in the #M2 spectrum, which promotes immunosuppression and healing. [9]

Involvement in disease

Aberrant CCL18 expression is observed in many diseases, and it is thought that these abnormal expression patterns play a key role in these diseases. [6] This table shows a list of all the diseases that CCL18 is involved in.

Breast cancer

The most understood disease that CCL18 is involved in is in breast cancer, where CCL18 induces metastasis of breast cancer cells by binding to PITPNM3. [15] Perhaps CCL18, in breast cancers, is acting as an immunosuppressive cytokine by generating T-regulatory cells, generating immunosuppressive dendritic cells and macrophages, and recruiting effector T-cells to these dendritic cells and macrophages to abolish their anti-cancer functions and allowing the cancer to escape the immune system.

Autoimmunity and hypersensitivity

CCL18 is highly expressed in T-helper 2 mediated hypersensitivity and autoimmune diseases, such as asthma and arthritis. [13] CCL18 is expressed at much higher levels in allergic patients compared to healthy patients and respond aggressively to innocuous antigens. [13] Allergic patients also had higher amounts of activated T-cells in the lungs, suggesting that CCL18 recruitment of these cells is contributing to hypersensitivity. In addition to lung hypersensitivities, these patterns were also observed in dermatitis patients. [6] Furthermore, a similar pattern was also observed in arthritis patients, where CCL18 was expressed at much higher rates by dendritic cells in affected patients. [22] However, in arthritis, perhaps the increased CCL18 is an attempt to suppress effector T-helper 1 cells that are self-reactive.

Related Research Articles

<span class="mw-page-title-main">CD80</span> Mammalian protein found in Homo sapiens

The Cluster of differentiation 80 is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is closely related to CD86, another B7 protein (B7-2), and often works in tandem. Both CD80 and CD86 interact with costimulatory receptors CD28, CTLA-4 (CD152) and the p75 neurotrophin receptor.

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.

<span class="mw-page-title-main">CCL7</span> Mammalian protein found in Homo sapiens

Chemokine 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.

<span class="mw-page-title-main">CCL20</span> Mammalian protein found in Homo sapiens

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.

<span class="mw-page-title-main">CCL21</span> Mammalian protein found in Homo sapiens

Chemokine ligand 21 (CCL21) is a small cytokine belonging to the CC chemokine family. This chemokine is also known as 6Ckine, exodus-2, and secondary lymphoid-tissue chemokine (SLC). CCL21 elicits its effects by binding to a cell surface chemokine receptor known as CCR7. The main function of CCL21 is to guide CCR7 expressing leukocytes to the secondary lymphoid organs, such as lymph nodes and Peyer´s patches.

<span class="mw-page-title-main">CCL22</span> Mammalian protein found in Homo sapiens

C-C motif chemokine 22 is a protein that in humans is encoded by the CCL22 gene.

<span class="mw-page-title-main">CCL19</span> Mammalian protein found in Homo sapiens

Chemokine ligand 19 (CCL19) is a protein that in humans is encoded by the CCL19 gene.

<span class="mw-page-title-main">CXCL9</span> Mammalian protein found in Homo sapiens

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.

CC chemokine receptors are integral membrane proteins that specifically bind and respond to cytokines of the CC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane (7-TM) proteins since they span the cell membrane seven times. To date, ten true members of the CC chemokine receptor subfamily have been described. These are named CCR1 to CCR10 according to the IUIS/WHO Subcommittee on Chemokine Nomenclature.

<span class="mw-page-title-main">CCL9</span> Mammalian protein found in Mus musculus

Chemokine ligand 9 (CCL9) is a small cytokine belonging to the CC chemokine family. It is also called macrophage inflammatory protein-1 gamma (MIP-1γ), macrophage inflammatory protein-related protein-2 (MRP-2) and CCF18, that has been described in rodents. CCL9 has also been previously designated CCL10, although this name is no longer in use. It is secreted by follicle-associated epithelium (FAE) such as that found around Peyer's patches, and attracts dendritic cells that possess the cell surface molecule CD11b and the chemokine receptor CCR1. CCL9 can activate osteoclasts through its receptor CCR1 suggesting an important role for CCL9 in bone resorption. CCL9 is constitutively expressed in macrophages and myeloid cells. The gene for CCL9 is located on chromosome 11 in mice.

<span class="mw-page-title-main">C-C chemokine receptor type 7</span> Protein-coding gene in the species Homo sapiens

C-C chemokine receptor type 7 is a protein that in humans is encoded by the CCR7 gene. Two ligands have been identified for this receptor: the chemokines ligand 19 (CCL19/ELC) and ligand 21 (CCL21). The ligands have similar affinity for the receptor, though CCL19 has been shown to induce internalisation of CCR7 and desensitisation of the cell to CCL19/CCL21 signals. CCR7 is a transmembrane protein with 7 transmembrane domains, which is coupled with heterotrimeric G proteins, which transduce the signal downstream through various signalling cascades. The main function of the receptor is to guide immune cells to immune organs by detecting specific chemokines, which these tissues secrete.

<span class="mw-page-title-main">C-C chemokine receptor type 6</span> Mammalian protein found in Homo sapiens

Chemokine receptor 6 also known as CCR6 is a CC chemokine receptor protein which in humans is encoded by the CCR6 gene. CCR6 has also recently been designated CD196. The gene is located on the long arm of Chromosome 6 (6q27) on the Watson (plus) strand. It is 139,737 bases long and encodes a protein of 374 amino acids.

<span class="mw-page-title-main">CCR8 (gene)</span> Protein-coding gene in the species Homo sapiens

Chemokine receptor 8, also known as CCR8, is a protein which in humans is encoded by the CCR8 gene. CCR8 has also recently been designated CDw198.

<span class="mw-page-title-main">CCR9</span> Protein-coding gene in the species Homo sapiens

C-C chemokine receptor type 9 is a protein that in humans is encoded by the CCR9 gene. This gene is mapped to the chemokine receptor gene cluster region. Two alternatively spliced transcript variants have been described.

<span class="mw-page-title-main">Signal-regulatory protein alpha</span> Protein-coding gene in the species Homo sapiens

Signal regulatory protein α (SIRPα) is a regulatory membrane glycoprotein from SIRP family expressed mainly by myeloid cells and also by stem cells or neurons.

<span class="mw-page-title-main">CCL4L1</span> Protein-coding gene in the species Homo sapiens

C-C motif chemokine 4-like is a protein that in humans is encoded by the CCL4L1 gene.

<span class="mw-page-title-main">CD200</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">MARCO</span> Protein-coding gene in the species Homo sapiens

Macrophage receptor with collagenous structure (MARCO) is a protein that in humans is encoded by the MARCO gene. MARCO is a class A scavenger receptor that is found on particular subsets of macrophages. Scavenger receptors are pattern recognition receptors (PRRs) found most commonly on immune cells. Their defining feature is that they bind to polyanions and modified forms of a type of cholesterol called low-density lipoprotein (LDL). MARCO is able to bind and phagocytose these ligands and pathogen-associated molecular patterns (PAMPs), leading to the clearance of pathogens and cell signaling events that lead to inflammation. As part of the innate immune system, MARCO clears, or scavenges, pathogens, which leads to inflammatory responses. The scavenger receptor cysteine-rich (SRCR) domain at the end of the extracellular side of MARCO binds ligands to activate the subsequent immune responses. MARCO expression on macrophages has been associated with tumor development and also with Alzheimer's disease, via decreased responses of cells when ligands bind to MARCO.

A macrophage-activating factor (MAF) is a lymphokine or other receptor based signal that primes macrophages towards cytotoxicity to tumors, cytokine secretion, or clearance of pathogens. Similar molecules may cause development of an inhibitory, regulatory phenotype. A MAF can also alter the ability of macrophages to present MHC I antigen, participate in Th responses, and/or affect other immune responses.

Chemorepulsion is the directional movement of a cell away from a substance. Of the two directional varieties of chemotaxis, chemoattraction has been studied to a much greater extent. Only recently have the key components of the chemorepulsive pathway been elucidated. The exact mechanism is still being investigated, and its constituents are currently being explored as likely candidates for immunotherapies.

References

  1. 1 2 3 ENSG00000278167, ENSG00000278006 GRCh38: Ensembl release 89: ENSG00000275385, ENSG00000278167, ENSG00000278006 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 1 2 Hieshima K, Imai T, Baba M, Shoudai K, Ishizuka K, Nakagawa T, Tsuruta J, Takeya M, Sakaki Y, Takatsuki K, Miura R, Opdenakker G, Van Damme J, Yoshie O, Nomiyama H (August 1997). "A novel human CC chemokine PARC that is most homologous to macrophage-inflammatory protein-1 alpha/LD78 alpha and chemotactic for T lymphocytes, but not for monocytes". J. Immunol. 159 (3): 1140–9. doi: 10.4049/jimmunol.159.3.1140 . PMID   9233607. S2CID   6071325.
  4. 1 2 Politz O, Kodelja V, Guillot P, Orfanos CE, Goerdt S (February 2000). "Pseudoexons and regulatory elements in the genomic sequence of the beta-chemokine, alternative macrophage activation-associated CC-chemokine (AMAC)-1". Cytokine. 12 (2): 120–6. doi:10.1006/cyto.1999.0538. PMID   10671296.
  5. ↑ Tasaki Y, Fukuda S, Iio M, Miura R, Imai T, Sugano S, Yoshie O, Hughes AL, Nomiyama H (February 1999). "Chemokine PARC gene (SCYA18) generated by fusion of two MIP-1alpha/LD78alpha-like genes". Genomics. 55 (3): 353–7. doi:10.1006/geno.1998.5670. PMID   10049593.
  6. 1 2 3 4 5 Schutyser E, Richmond A, Van Damme J (July 2005). "Involvement of CC chemokine ligand 18 (CCL18) in normal and pathological processes". J. Leukoc. Biol. 78 (1): 14–26. doi:10.1189/jlb.1204712. PMC   2665283 . PMID   15784687.
  7. 1 2 3 4 Bellinghausen I, Reuter S, Martin H, Maxeiner J, Luxemburger U, Türeci Ö, Grabbe S, Taube C, Saloga J (December 2012). "Enhanced production of CCL18 by tolerogenic dendritic cells is associated with inhibition of allergic airway reactivity". J. Allergy Clin. Immunol. 130 (6): 1384–93. doi: 10.1016/j.jaci.2012.08.039 . PMID   23102918.
  8. ↑ Ferrara G, Bleck B, Richeldi L, Reibman J, Fabbri LM, Rom WN, Condos R (December 2008). "Mycobacterium tuberculosis induces CCL18 expression in human macrophages". Scand. J. Immunol. 68 (6): 668–74. doi: 10.1111/j.1365-3083.2008.02182.x . PMID   18959625.
  9. 1 2 3 4 Schraufstatter IU, Zhao M, Khaldoyanidi SK, Discipio RG (April 2012). "The chemokine CCL18 causes maturation of cultured monocytes to macrophages in the M2 spectrum". Immunology. 135 (4): 287–98. doi:10.1111/j.1365-2567.2011.03541.x. PMC   3372745 . PMID   22117697.
  10. 1 2 3 Vulcano M, Struyf S, Scapini P, Cassatella M, Bernasconi S, Bonecchi R, Calleri A, Penna G, Adorini L, Luini W, Mantovani A, Van Damme J, Sozzani S (April 2003). "Unique regulation of CCL18 production by maturing dendritic cells". J. Immunol. 170 (7): 3843–9. doi: 10.4049/jimmunol.170.7.3843 . PMID   12646652.
  11. ↑ Adema GJ, Hartgers F, Verstraten R, de Vries E, Marland G, Menon S, Foster J, Xu Y, Nooyen P, McClanahan T, Bacon KB, Figdor CG (June 1997). "A dendritic-cell-derived C-C chemokine that preferentially attracts naive T cells". Nature. 387 (6634): 713–7. Bibcode:1997Natur.387..713A. doi:10.1038/42716. hdl: 2066/27106 . PMID   9192897. S2CID   4311897.
  12. ↑ Chenivesse C, Chang Y, Azzaoui I, Ait Yahia S, Morales O, Plé C, Foussat A, Tonnel AB, Delhem N, Yssel H, Vorng H, Wallaert B, Tsicopoulos A (July 2012). "Pulmonary CCL18 recruits human regulatory T cells". J. Immunol. 189 (1): 128–37. doi: 10.4049/jimmunol.1003616 . hdl: 20.500.12210/39240 . PMID   22649201.
  13. 1 2 3 4 de Nadaï P, Charbonnier AS, Chenivesse C, Sénéchal S, Fournier C, Gilet J, Vorng H, Chang Y, Gosset P, Wallaert B, Tonnel AB, Lassalle P, Tsicopoulos A (May 2006). "Involvement of CCL18 in allergic asthma". J. Immunol. 176 (10): 6286–93. doi: 10.4049/jimmunol.176.10.6286 . PMID   16670340.
  14. ↑ Li HY, Cui XY, Wu W, Yu FY, Yao HR, Liu Q, Chen JQ (October 2013). "Pyk2 and Src mediate signaling to CCL18-induced breast cancer metastasis". J. Cell. Biochem. 115 (3): 596–603. doi:10.1002/jcb.24697. PMID   24142406. S2CID   8411960.
  15. 1 2 Chen J, Yao Y, Gong C, Yu F, Su S, Chen J, Liu B, Deng H, Wang F, Lin L, Yao H, Su F, Anderson KS, Liu Q, Ewen ME, Yao X, Song E (April 2011). "CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3". Cancer Cell. 19 (4): 541–55. doi:10.1016/j.ccr.2011.02.006. PMC   3107500 . PMID   21481794.
  16. ↑ Catusse J, Wollner S, Leick M, Schröttner P, Schraufstätter I, Burger M (November 2010). "Attenuation of CXCR4 responses by CCL18 in acute lymphocytic leukemia B cells". J. Cell. Physiol. 225 (3): 792–800. doi:10.1002/jcp.22284. PMID   20568229. S2CID   24889239.
  17. 1 2 Islam SA, Ling MF, Leung J, Shreffler WG, Luster AD (September 2013). "Identification of human CCR8 as a CCL18 receptor" (PDF). J. Exp. Med. 210 (10): 1889–98. doi:10.1084/jem.20130240. PMC   3782048 . PMID   23999500.
  18. ↑ Kodelja V, Müller C, Politz O, Hakij N, Orfanos CE, Goerdt S (February 1998). "Alternative macrophage activation-associated CC-chemokine-1, a novel structural homologue of macrophage inflammatory protein-1 alpha with a Th2-associated expression pattern". J. Immunol. 160 (3): 1411–8. doi: 10.4049/jimmunol.160.3.1411 . PMID   9570561. S2CID   46401617.
  19. ↑ Bruna-Romero O, Schmieg J, Del Val M, Buschle M, Tsuji M (March 2003). "The dendritic cell-specific chemokine, dendritic cell-derived CC chemokine 1, enhances protective cell-mediated immunity to murine malaria". J. Immunol. 170 (6): 3195–203. doi: 10.4049/jimmunol.170.6.3195 . PMID   12626578.
  20. ↑ Lindhout E, Vissers JL, Hartgers FC, Huijbens RJ, Scharenborg NM, Figdor CG, Adema GJ (March 2001). "The dendritic cell-specific CC-chemokine DC-CK1 is expressed by germinal center dendritic cells and attracts CD38-negative mantle zone B lymphocytes". J. Immunol. 166 (5): 3284–9. doi: 10.4049/jimmunol.166.5.3284 . PMID   11207283.
  21. ↑ Azzaoui I, Yahia SA, Chang Y, Vorng H, Morales O, Fan Y, Delhem N, Ple C, Tonnel AB, Wallaert B, Tsicopoulos A (September 2011). "CCL18 differentiates dendritic cells in tolerogenic cells able to prime regulatory T cells in healthy subjects". Blood. 118 (13): 3549–58. doi: 10.1182/blood-2011-02-338780 . PMID   21803856.
  22. ↑ Radstake TR, van der Voort R, ten Brummelhuis M, de Waal Malefijt M, Looman M, Figdor CG, van den Berg WB, Barrera P, Adema GJ (March 2005). "Increased expression of CCL18, CCL19, and CCL17 by dendritic cells from patients with rheumatoid arthritis, and regulation by Fc gamma receptors". Ann. Rheum. Dis. 64 (3): 359–67. doi:10.1136/ard.2003.017566. PMC   1755402 . PMID   15331393.
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