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Endothelial protein C receptor is over-expressed in rheumatoid arthritic (RA) synovium and mediates the anti-inflammatory effects of activated protein C in RA monocytes
  1. Meilang Xue (mlxue{at}med.usyd.edu.au)
  1. The University of Sydney, Australia
    1. Lyn March (lynmar{at}med.usyd.edu.au)
    1. The University of Sydney, Australia
      1. Philip N Sambrook (sambrook{at}med.usyd.edu.au)
      1. The University of Sydney, Australia
        1. Kenji Fukudome (fukudome{at}cc.saga-u.ac.jp)
        1. Saga Medical School, Japan
          1. Christopher J Jackson (cjackson{at}med.usyd.edu.au)
          1. The University of Sydney, Australia

            Abstract

            Objectives: i) To investigate whether inflammatory synovial tissues from patients with rheumatoid arthritis (RA) express endothelial protein C receptor (EPCR) and ii) to determine the major cell type (s) that EPCR is associated with and whether EPCR functions to mediate the effects of activated protein C (APC) on these cells.

            Methods: EPCR, CD68 and PC/APC in synovial tissues were detected by immunostaining and in situ PCR. Monocytes were isolated from peripheral blood of patients with RA and treated with APC, lipopolysaccharide (LPS), and/or EPCR blocking antibody RCR252. Cells and supernatants were collected for RT-PCR, western blotting, enzyme-linked immuosorbent assay and chemotaxis assay.

            Results: EPCR was expressed by both OA and RA synovial tissues but was markedly increased in RA synovium. EPCR was colocalized with PC/APC mostly on CD68 positive cells in synovium. In RA monocytes, APC upregulated EPCR expression and reduced monocyte chemoattractant protein-1-induced chemotaxis of monocytes by approximately 50%. APC also completely suppressed LPS-stimulated NF-κB activation and attenuated TNF-α protein by more than 40% in RA monocytes. The inhibitory effects of APC were reversed by RCR252, indicating that EPCR is required.

            Conclusions: Our results demonstrate for the first time that EPCR is expressed by synovial tissues, particularly in RA, where it co-localizes with PC/APC on monocytes/macrophages. In addition, APC inhibits the migration and activation of RA monocytes via EPCR. These inhibitory effects on RA monocytes suggest that PC pathway may have a beneficial therapeutic effect in RA.

            • activated protein C
            • endothelial protein C receptor
            • migration and activation
            • monocytes
            • rheumatoid arthritis

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