CCL18 Activates Fibroblast-like Synoviocytes in Patients with Rheumatoid Arthritis

Abstract

To the Editor: Fibroblast-like synoviocytes (FLS) proliferate in the synovial tissue of patients with rheumatoid arthritis (RA), and contribute to chronic inflammation and the destruction of articular cartilage due to the production of a variety of cytokines, chemokines, and matrix metalloproteinases (MMP)1. The expression of CC chemokine ligand 18 (CCL18) was shown to be increased in the RA synovium2,3; however, the pathogenic role of CCL18 remains unclear. In this study, we investigated the expression of a recently identified receptor for CCL18, phosphatidylinositol transfer membrane-associated phosphatidylinositol transfer protein 3 (PITPNM3)4 in the RA synovium, and the stimulatory effects of CCL18 on FLS. Synovial tissue samples were obtained from patients with RA (n = 4) and osteoarthritis (OA) (n = 4) undergoing joint replacement surgery. RA patients were a median 65 years old (range 48–85 yrs), with median disease duration 9 years (range 2.5–30 yrs) and median C-reactive protein level 1.23 mg/dl (range 0.68–2.85). All RA patients were positive for rheumatoid factor and anticitrullinated protein antibodies. All subjects provided informed consent. The experimental protocol was approved in advance by the Ethics Committee of Tokyo Medical and Dental University. CCL18-positive cells were observed in the synovial lining, sublining, and perivascular regions of the RA synovium (Figure 1A). CCL18 expression was minimal in the OA synovium (Figure 1C). Western blotting analysis showed that CCL18 expression was significantly higher in the RA synovium than in the OA synovium (Figure 1E, 1F). Double-immunofluorescence staining revealed that most CD68-positive macrophages expressed CCL18 (Figures 1G–1I), and von Willebrand factor (vWF)-positive vascular endothelial cells were also … Address correspondence to Dr. T. Nanki, Department of Medicine and Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail: nanki.rheu{at}tmd.ac.jp