CCL18

The gene of CCL18 is most similar to CCL3. 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. 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. 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. == Sources ==

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, T-regulatory cells, T-helper 2 cells, both immunosuppressive and immature Dendritic Cells, basophils, and B-cells (naïve and effector). 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. 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. 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. 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. Furthermore, CCL18 binding is competitive with CCR8's previously described ligand, CCL1, further suggesting that CCL18 binds physiologically with CCR8.) 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 and other hypersensitivity diseases, Finally, CCL18 is expressed by dendritic cells in the germinal center of inflamed lymph nodes, and recruits naïve B-cells for antigen presentation. 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. Furthermore, exposure to CCL18 by macrophages causes them to mature in the #M2 spectrum, which promotes immunosuppression and healing. == 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. However, in arthritis, perhaps the increased CCL18 is an attempt to suppress effector T-helper 1 cells that are self-reactive. == References ==