Expression and Cellular Localization of the CC Chemokines PARC and ELC in Human Atherosclerotic Plaques

Abstract

Local immune responses are thought to play an important role in the development of atherosclerosis. Histological studies have shown that human atherosclerotic lesions contain T lymphocytes throughout all stages of development, many of which are in an activated state. A number of novel CC chemokines have been described recently, which are potent chemoattractants for lymphocytes: PARC (pulmonary and activation-regulated chemokine), ELC (EBI1-ligand chemokine), LARC (liver and activation-regulated chemokine), and SLC (secondary lymphoid-tissue chemokine). Using reverse transcriptase-polymerase chain reaction and in situ hybridization, we have found gene expression for PARC and ELC but not for LARC or SLC in human atherosclerotic plaques. Immunohistochemical staining of serial plaque sections with specific cell markers revealed highly different expression patterns of PARC and ELC. PARC mRNA was restricted to CD68+ macrophages (n = 14 of 18), whereas ELC mRNA was widely expressed by macrophages and intimal smooth muscle cells (SMC) in nearly all of the lesions examined (n = 12 of 14). ELC mRNA was also found to be expressed in the medial SMC wall of highly calcified plaques (n = 4). Very low levels of ELC mRNA expression could also be detected in normal mammary arteries but no mRNA expression for PARC was detected in these vessels (n = 4). In vitro, ELC mRNA was found to be up-regulated in aortic SMC stimulated with tumor necrosis factor-a and interferon-gamma but not in SMC stimulated with serum. Both PARC and ELC mRNA were expressed by monocyte-derived macrophages but not monocytes. The expression patterns of PARC and ELC mRNA in human atherosclerotic lesions suggest a potential role for these two recently described CC chemokines in attracting T lymphocytes into atherosclerotic lesions.

Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention

“…12 There have been several reports on elevated levels of CCL18 in human disease, for example, atherosclerosis, active hepatitis C infection, hypersensitive pneumonitis, allergic contact hypersensitivity, septic as well as rheumatoid arthritis, and ovarian carcinoma. [24][25][26][27][28][29][30] Different detection methods have been used in the previous studies; in some investigations CCL18 mRNA was detected either by reverse transcription-polymerase chain reaction analysis or in situ hybridization 24,25,27,29,30 and in other studies ELISAs were used to measure CCL18 protein concentration in synovial or ascitic fluid. 26,28 To our knowledge this is the first report on chronically elevated plasma levels of CCL18 in a disease condition.…”

Identification of Biologically Active Chemokine Isoforms from Ascitic Fluid and Elevated Levels of CCL18/Pulmonary and Activation-regulated Chemokine in Ovarian Carcinoma

“…Moreover, no homologue for human CCL18/PARC has been found yet in any other species. Human CCL18/PARC mRNA expression was observed in monocytic and dendritic cells (5, 20 -22), in normal lung, in hypersensitivity pneumonitis-affected lungs, in germinal centers of regional lymph nodes and tonsils, in atherosclerotic plaques, in inflamed liver, and in the dermis of contact hypersensitivity patients (5,20,(42)(43)(44)(45). However, little is known yet about the CCL18/PARC protein levels in vitro or in vivo.…”

Mature Dendritic Cells Express Functional Thrombin Receptors Triggering Chemotaxis and CCL18/Pulmonary and Activation-Regulated Chemokine Induction

“…CCL18 seems to be associated with a number of pathological conditions including malignances and chronic inflammation (19). Moreover, CCL18 expression is also detected in atherosclerotic lesions (21). In monocytes in vitro its production is induced by LPS and CD40L (53), whereas in iDC it is activated by anti-inflammatory stimuli such as IL-10 or vitamin D 3 (54,55).…”

“…Total RNA (1.5 g) was used and specific primers for PAR1, PAR2, PAR3, PAR4, and GAPDH (ThermoHybaid) for normalization (5). Primers for CCL18 were as described elsewhere (21). To exclude genomic DNA contamination, all RNA samples were pretreated with DNase I (Invitrogen).…”