Volume 4 Supplement 1

22nd European Workshop for Rheumatology Research

Open Access

Constitutively activated N-Ras stimulates LFA-1-dependent adhesion in rheumatoid arthritis synovial fluid T lymphocytes

  • KA Reedquist1,
  • PHJ Remans2,
  • SI Gringhuis2,
  • KMT de Bruyn3,
  • S Rangarajan3,
  • JL Bos3 and
  • PP Tak1
Arthritis Research & Therapy20024(Suppl 1):49

https://doi.org/10.1186/ar491

Received: 15 January 2002

Published: 4 February 2002

Synovial fluid (SF) T lymphocytes isolated from rheumatoid arthritis (RA) patients display constitutive activation of the integrin LFA-1. LFA-1-dependent T cell interactions with ICAM-bearing fibroblast-like synoviocytes and macrophages contribute to the inflammatory state of the joint via retention of T lymphocytes in the synovium and induction of inflammatory cytokines. SF components, notably TGF-β, are sufficient and required to sustain activation of LFA-1 in SF T lymphocytes, but little is known about the intracellular signalling pathways regulating LFA-1-dependent adhesion in SF T lymphocytes. We have recently found that deregulated signalling via the small GTPases Ras and Rap1 is responsible for chronic oxidative stress in SF T lymphocytes. Although activated Rap1 is a critical mediator of T cell receptor and CD31 -stimulated LFA-1 adhesion, SF T lymphocytes adhere via LFA-1 in the complete absence of Rap1 signalling. We find that both N-Ras and K-Ras isoforms of Ras are constitutively activated in SF T cells, and that transient expression of activated N-Ras, but not K-Ras or H-Ras, stimulates LFA-1-dependent adhesion in Jurkat T lymphocytes. Adhesion induced by N-Ras is insensitive to overexpression of the Rap1 negative regulatory protein RapGAP, consistent with the observation that SF T cells are highly adherant despite undetectable levels of activated Rap1. We provide pharmacological evidence indicating that N-Ras and Rap1 induce adhesion by distinct signalling mechanisms. Identification of N-Ras as a key intracellular signalling protein mediating lymphocyte retention in RA joints provides potential targets for new therapeutic strategies for RA.

Authors’ Affiliations

(1)
Academic Medical Center
(2)
Leiden University Medical Cent
(3)
Utrecht Univ Medical Center

Copyright

© BioMed Central Ltd 2002

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