Ccl18

Chemokines, a subgroup of cytokines, are small (size between 8 and 10 kDa), chemotactically active proteins (signal proteins). They are common in all vertebrates, some virus types and bacteria. In humans, about 50 chemokines are currently known. A strongly conserved structural feature of all chemokines is a fixed group of cysteine residues that is stabilized by 1 or 2 disulfide bridges. This key structural position in the molecule is responsible for its fixed 3-dimensional structure.

In the CC chemokines, the cysteines follow each other directly (see figure), in the CXC chemokines they are separated (CC = acronym for cysteine-cysteine) by 1, in the CXXXC chemokines by 3 other amino acids. We show that CCL15 is processed in human synovial fluid by matrix metalloproteinases (MMPs) and serine proteases. They transmit their signals by binding to chemokine receptors via G-proteins. Some chemokines have a pro-inflammatory effect, others have a regulatory effect on the formation, homeostasis and proliferation of tissues.

CCL18, also known as "C-C motif chemokine ligand 18", is a small, human cytokine belonging to the CC chemokine family. The chemokine has anti-inflammatory as well as pro-inflammatory and oncogenic-proliferative properties. The coding CCL18 gene is located on chromosome 17 in humans and shows a large molecular correspondence with the CCL3 gene.

CCL18 is produced by numerous mainly antigen-presenting immune cells (monocytes, macrophages, dendritic cells). Interleukins 4, IL-10 and IL-13 (cytokines of T-helper type 2 reactivity) activate, interferon-gamma suppresses the production of the cytokine. Furthermore, CCL18 is expressed by fibroblasts which is important for wound healing. CCL18 is ligand for the receptors PITPNM3, GPR30 and CCR8.

The chemokine acts chemotactically on naive and regulatory T cells (Treg) on TH2 cells, on B cells, immunosuppressive and immature dendritic cells and basophilic granulocytes. CCL18 attracts naive T cells towards dendritic cells and activates macrophages in lymph nodes.

CCL18 is detected phyiologically with significant concentration mainly in lungs, lymph nodes, placenta, bone marrow. CCL18 plays a role in pulmonary fibrosis and atopic eczema.

Furthermore, the cytokine in the synovial fluid of patients with rheumatoid but also septic arthritis is significantly elevated; the same applies to the urine of patients with lysosomal storage disease, Gaucher's disease (E75.2), in which glucocerebrosides are accumulated in the monocyte-macrophage system due to a glucocerebrosidase deficiency.

CCL18 is upregulated in numerous malignant tumors. Tumor-induced CCL18 expression is sometimes (but not consistently) associated with a poor prognosis.

High levels of CCL18 were found in gastric carcinomas, ovarian carcinomas (detectable in ascites punctates), breast carcinomas, colorectal carcinomas (in this carcinoma high levels of CCL18 are associated with a favourable prognosis), bladder carcinomas, hepatocellular carcinomas, etc.

In breast carcinoma, CCL18 is produced by "tumour-associated macrophages - TAMs" and together with VEGF regulates angiogenesis and tumour progression. To what extent this can lead to therapeutic approaches is currently still unclear.

1. Boot RG et al (2006) CCL18: a urinary marker of Gaucher cell burden in Gaucher patients. J Inherit Metab Dis 29:564-571.
2. Hou X et al (2016) CCL18 promotes the invasion and migration of gastric cancer cells via ERK1/2/NF-κB signaling pathway. Tumour Biol 37:641-651.
3. Lane D et al (2016) CCL18 from ascites promotes ovarian cancer cell migration through proline-rich tyrosine kinase 2 signaling. Mol Cancer 15:58.
4. Lin Z et al (2015) CCL18/PITPNM3 enhances migration, invasion, and EMT through the NF-κB signaling pathway in hepatocellular carcinoma. Tumour Biol 37:3461-3468.
5. Lin L et al (2015) CCL18 from tumor-associated macrophages promotes angiogenesis in breast cancer. Oncotarget 6:34758-3473.
6. Lopa S et al (2015) Arthritic and non-arthritic synovial fluids modulate IL10 and IL1RA gene expression in differentially activated primary human monocytes. Osteoarthritis cartilage 23:1853 1857.
7. Miyake M et al (2013) Investigation of CCL18 and A1AT as potential urinary biomarkers for bladder cancer detection. BMC Urol 13:42.
8. Schutyser E et al (2005) Involvement of CC chemokine ligand 18 (CCL18) in normal and pathological processes. J Leukoc Biole 78:14-26.
9. Tsicopoulos A et al. (2013) Role of CCL18 in asthma and lung immunity. Clin Exp Allergy 43:716-722.
10. Yuan R et al (2013) CCL18 as an independent favorable prognostic biomarker in patients with colorectal cancer. J Surg Res 183:163-169.