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AB0108 BETA-1 integrin is a critical mediator of TLR2-induced cell migration and invasion in RA
  1. T. McGarry,
  2. M. Connolly,
  3. W. Gao,
  4. J. McCormick,
  5. D. Veale,
  6. U. Fearon
  1. Rheumatology, Dublin Academic Medical Center, Dublin, Ireland

Abstract

Background Inflammatory arthritis (IA) is a chronic disease characterised by inflammation and proliferation of synovial tissue, leading to progressive degradation of articular cartilage and bone.

Objectives This aim of this study was to investigate the role of β1-integrin in mediating TLR2-induced cytoskeletal rearrangement, cell migration and invasion processes in vitro.

Methods β-integrin expression (β1-4, β6, avβ5, a5β1), cytoskeletal rearrangement and RhoGTPase Rac1 activation in response to PAM3Cysk4 (1μg/ml) (TLR2-ligand) were assessed by a multiplex adhesion binding assay, F-actin immunofluorescent staining and Rac-1 pull down assays/Western blot. Pam3CSK4 induced cell migration, invasion and Rac1 activation was assessed by wound repair assays, transwell matrigel™ invasion chambers and Pulldown/western blot in the presence or absence of anti-β1 integrin (10μg/ml) or IgG control antibody (10μg/ml).

Results Pam3CSK4 specifically induced β1-integrin binding (p<0.05), with no effect observed for β2-4, β6, avβ5 or a5β1. Pam3CSK4 induced cytoskeletal disassembly, inducing microspike and filopodia formation. Furthermore Pam3CSK4 induced Rac1 activation, which is critically involved in cytoskeletal dynamics and cell movement. At a functional level Pam3CSK4 induced cell migration and invasion of RASFC (p<0.05). Pam3CSK4-regulated cell migration and invasion processes were inhibited in the presence of anti-β1 integrin (p<0.05), with no effect observed for IgG control. Furthermore Pam3CSK4 induced Rac-1 activation was also inhibited in the presence of anti-β1 integrin.

Conclusions TLR2 activation induces cell migrational and invasive mechanisms which are specifically mediated through β1-integrin-induced cytoskeletal pathways.

Disclosure of Interest T. McGarry: None Declared, M. Connolly: None Declared, W. Gao: None Declared, J. McCormick: None Declared, D. Veale Grant/Research support from: Wyeth, GSK, Abbott, Opsona, Consultant for: Wyeth, GSK, Abbott, Pfizer, Schering Plough, Centocor, Speakers Bureau: Wyeth, GSK, Abbott, Pfizer. Schering Plough, Centocor, Mundipharma, U. Fearon: None Declared

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