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Endothelial protein C receptor is overexpressed in rheumatoid arthritic (RA) synovium and mediates the anti-inflammatory effects of activated protein C in RA monocytes
  1. Meilang Xue1,
  2. Lyn March1,
  3. Philip N Sambrook1,
  4. Kenji Fukudome2,
  5. Christopher J Jackson1
  1. 1
    Sutton Arthritis Research Laboratories, Department of Rheumatology, Institute of Bone and Joint Research, University of Sydney at Royal North Shore Hospital, St Leonards NSW, Australia
  2. 2
    Department of Immunology, Saga Medical School, Nabeshima, Saga, Japan
  1. Dr Meilang Xue, Sutton Arthritis Research Laboratories, Level 1, Block 4, University of Sydney at Royal North Shore Hospital, St Leonards NSW, 2065 Australia; mlxue{at}med.usyd.edu.au

Abstract

Objectives: (1) To investigate whether inflammatory synovial tissues from patients with rheumatoid arthritis (RA) express endothelial protein C receptor (EPCR) and (2) 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 colocalised 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-localises 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.

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Footnotes

  • Competing interests: None declared.

  • Abbreviations:
    APC
    activated protein C
    EPCR
    express endothelial protein C
    IL
    interleukin
    LPS
    lipopolysaccharide
    MCP
    monocyte chemoattractant protein
    PC
    protein C
    RA
    rheumatoid arthritis
    TNF
    tumour necrosis factor

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