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Ann Rheum Dis 70:366-372 doi:10.1136/ard.2010.133587
  • Basic and translational research
  • Extended report

Endothelial activation and apoptosis mediated by neutrophil-dependent interleukin 6 trans-signalling: a novel target for systemic sclerosis?

Open Access
  1. Robert J Moots1
  1. 1School of Clinical Sciences, University of Liverpool, Liverpool, UK
  2. 2School of Biological Sciences, University of Liverpool, Liverpool, UK
  1. Correspondence to Professor Robert J Moots, Academic Rheumatology, Clinical Sciences Centre, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, UK; r.j.moots{at}liv.ac.uk
  • Accepted 16 September 2010
  • Published Online First 10 November 2010

Abstract

Objectives Systemic sclerosis (SSc) is a connective tissue disease associated with significant morbidity and mortality and generally inadequate treatment. Endothelial cell activation and apoptosis are thought to be pivotal in the pathogenesis of this disease, but the mechanisms that mediate this remain unknown.

Methods Human dermal microvascular endothelial cells were cultured with healthy control neutrophils in the presence of 25% healthy control or SSc serum for 24 h. Apoptosis was measured by annexin V-FITC binding and endothelial cell activation was measured using an allophycocyanin-conjugated E-selectin antibody. Fluorescence was quantified and localised using confocal microscopy.

Results SSc serum resulted in significantly increased apoptosis (p=0.006) and E-selectin expression (p=0.00004) in endothelial cells compared with control serum, effects that were critically dependent on the presence of neutrophils. Recombinant interleukin 6 (IL-6) reproduced these findings. Immunodepletion of IL-6 and the use of an IL-6 neutralising antibody decreased the effect of SSc serum on E-selectin expression. Soluble gp130, which specifically blocks IL-6 trans-signalling, negated the effect of SSc serum on both E-selectin expression and apoptosis.

Conclusions SSc serum induces endothelial cell activation and apoptosis in endothelial cell-neutrophil co-cultures, mediated largely by IL-6 and dependent on the presence of neutrophils. Together with other pathologically relevant effects of IL-6, these data justify further exploration of IL-6 as a therapeutic target in SSc.

Footnotes

  • SWE and RJM contributed equally to this work

  • Funding This work was funded by a Medical Research Council Clinical Training Fellowship held by TCB. The work was not in any part funded by interested parties in the pharmaceutical industry. The Aintree Arthritis Trust funded publication of this transcript.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Sefton research ethics committee, Liverpool, UK.

  • Provenance and peer review Not commissioned; externally peer reviewed.

This paper is freely available online under the BMJ Journals unlocked scheme, see http://ard.bmj.com/info/unlocked.dtl