Disease relevance of CCL18

• Genetic variation in the CCL18-CCL3-CCL4 chemokine gene cluster influences HIV Type 1 transmission and AIDS disease progression [1].
• Genomic DNAs from >3,000 participants enrolled in five United States-based natural-history cohorts with acquired immunodeficiency syndrome (AIDS) were genotyped for 21 single-nucleotide polymorphisms (SNPs) in a 47-kb interval on chromosome 17q12 containing the genes CCL3, CCL4, and CCL18 [1].
• Immunostaining showed CCL18 expression in tumor-infiltrating cells with monocyte/macrophage morphology but not in the ovarian carcinoma cells [2].
• PARC/CCL18 is a plasma CC chemokine with increased levels in childhood acute lymphoblastic leukemia [3].
• These findings suggest that monocytic cells respond to Gram-positive bacterial infection by the production of CCL18/PARC in the synovial cavity [4].
• Flow cytometry revealed an increase in the percentage of CCL18-positive alveolar macrophages and an increase in the CCL18 fluorescence intensity per cell in patients with fibrotic lung diseases [5].

High impact information on CCL18

• We show that DC-CK1, in contrast to RANTES, MIP-1alpha and interleukin-8, preferentially attracts naive T cells (CD45RA+) [6].
• Here we report the identification and characterization of a C-C chemokine (DC-CK1) that is specifically expressed by human dendritic cells at high levels [6].
• The specific expression of DC-CK1 by dendritic cells at the site of initiation of an immune response, combined with its chemotactic activity for naive T cells, suggests that DC-CK1 has an important rule in the induction of immune responses [6].
• METHODS: We identified a specific gene of interest, chemokine (C-C motif) ligand 18 (CCL18), on the basis of a high absolute standardized log Cox hazard ratio, a high variance in expression among all tumor samples, and putative biologic function [7].
• We found that CCL18 was expressed by a subpopulation of tumor-associated macrophages that were preferentially located at the tumor invasion front [7].

Chemical compound and disease context of CCL18

• In vivo, topical exposure to the relevant allergen or the superantigen staphylococcal enterotoxin B, resulted in a significant induction of CCL18 in atopic dermatitis patients [8].

Biological context of CCL18

• Immunochemistry revealed CD68(+) monocytes/macrophages as the main CCL18/PARC-producing cell type in both PBMC and arthritic synovial tissue [4].
• 2. Dot-plot comparison suggested that the PARC gene had been generated by fusion of two MIP-1alpha-like genes with deletion and selective usage of exons [9].
• We investigated the involvement of CCL18 in the regulation of bone marrow hematopoiesis [10].
• Moreover, CCL18 expression is associated with an atopic dermatitis phenotype when compared with other chronic inflammatory skin diseases [8].
• The MNZ and GC showed upregulation of CCL20 and CCL18 respectively [11].

Anatomical context of CCL18

• Therefore, CCL18 may act as a chemotactic signal that promotes the colocalization of immature DC with naive T lymphocytes in an IL-10-dominated environment with the consequent generation of T regulatory cells [12].
• Unique regulation of CCL18 production by maturing dendritic cells [12].
• In ascitic fluids from patients with ovarian carcinoma (n = 12), significantly higher levels of CXCL8 and CCL18 (2.0 versus 0.7 ng/ml (p = 0.01) and 120 versus 44 ng/ml (p = 0.0002), respectively) were detected compared with those in nonovarian carcinoma patients (n = 12) [2].
• In contrast to CXCL8, CCL18 was not inducible in carcinoma cell lines [2].
• Binding analysis using PARC fused with alkaline phosphatase-(His)6 showed the presence of a single class of receptors for PARC on lymphocytes with a Kd of 1.9 nM and 590 sites/cell [13].

Associations of CCL18 with chemical compounds

• In contrast, FcgammaR stimulation inhibited the IL-10- and LPS-mediated induction of CCL18 [14].
• Furthermore, in nonatopic NiSO4-sensitized individuals, only relevant allergen but not irritant exposure resulted in the induction of CCL18 [8].
• Functionally, CCL18 preferentially attracted in vitro-polarized Th2 cells and basophils, but not eosinophils and Th1 cells, and induced basophil histamine and intracellular calcium release [15].
• Out of the three immunomodulatory drugs tested, Dx downregulates PARC mRNA expression in BALF cells in vitro [16].
• A combination of total protein, glucose, IL-8, PARC and IP-10 CSF levels proved to be most discriminative between LM and non-LM patients [17].

Regulatory relationships of CCL18

• Identification of biologically active chemokine isoforms from ascitic fluid and elevated levels of CCL18/pulmonary and activation-regulated chemokine in ovarian carcinoma [2].
• IL-10 also induced CCL18 secretion in blood myeloid DC [12].
• Selective induction of CCL18/PARC by staphylococcal enterotoxins in mononuclear cells and enhanced levels in septic and rheumatoid arthritis [4].
• Expression of AMAC-1 is inhibited by IFN-gamma while glucocorticoids exert a slightly positive synergistic effect in combination with IL-4 [18].
• Conditioned media from CCL18-treated mature monocytes fostered colony-promoting activity that increased the number of colonies formed by hematopoietic progenitor cells [10].

Other interactions of CCL18

• MIP4 may therefore use chemokine receptor agonism and antagonism to control leukocyte movement in vivo [19].
• Surprisingly, the unmodified MIP4 protein, which is known to act as a T cell chemoattractant, also exhibits this CCR3 antagonistic activity, although to a lesser extent than Met-Ckbeta7, but to a level that may be of physiological relevance [19].
• IL-10 and vitamin D(3), two known inhibitors of DC differentiation and function, strongly promoted CCL18 secretion, whereas IFN-gamma, a costimulator of DC function, inhibited its production [12].
• In synovial fluids from septic and rheumatoid arthritis patients, fourfold-enhanced CCL18/PARC levels (150 ng/ml) were detected compared to those in crystal-induced arthritis and osteoarthritis [4].
• In temporal arteries affected by giant cell arteritis, DCs are highly enriched and activated and have matured into fully differentiated cells producing the chemokines, CCL18, CCL19, and CCL21 [20].

Analytical, diagnostic and therapeutic context of CCL18

• In situ hybridization analyses showed that alveolar macrophages, follicular dendritic cells in the germinal centers of regional lymph nodes, and peripheral blood monocytes stimulated with LPS express PARC mRNA [13].
• In multivariate analysis, tumor stage and CCL18 levels were independent prognostic factors for predicting both overall and disease-free survival [7].
• In bronchoalveolar lavages from untreated asthmatic allergic patients, CCL18 was highly increased compared with controls [15].
• Prestimulation of primary T lymphocytes with CCL18 in vitro caused an up-regulation of TGFbeta1 and collagen production in T lymphocyte/fibroblast cocultures [21].
• Measurements and Main Results: Spontaneous CCL18 production by BAL-derived cells was markedly increased in patients with pulmonary fibrosis and correlated negatively with pulmonary function test parameters [22].

References