Get access

Tenascin-C is increased in atherothrombotic stroke patients and has an anti-inflammatory effect in the human carotid artery

Authors

  • Paula Clancy,

    Corresponding author
    1. Health practitioners And Researchers Together-Blood, Endothelium And Tissue (HART-BEAT), Australian Institute for Tropical Health and Medicine, School of Veterinary and Biomedical Sciences, James Cook University, Townsville, QLD, Australia
    • Address for correspondence: Paula Clancy, PhD, HART-BEAT, AITHM, School of Veterinary and Biomedical Sciences, James Cook University, Townsville, QLD, 4811 Australia. Tel: +61-7-47813295; E-mail: paula.clancy@jcu.edu.au.

    Search for more papers by this author
  • Lisa F. Lincz,

    1. Hunter Haematology Research Group, Calvary Mater Newcastle Hospital, Waratah, NSW, Australia
    Search for more papers by this author
  • Jane Maguire,

    1. Faculty of Health and Medicine, School of Nursing and Midwifery, University of Newcastle, University Drive, Callaghan, NSW, Australia
    Search for more papers by this author
  • Mark McEvoy,

    1. University of Newcastle, School of Medicine and Public Health, New Lambton, NSW, Australia
    Search for more papers by this author
  • Simon A. Koblar,

    1. Stroke Research Programme, School of Medicine, The Queen Elizabeth Hospital (TQEH) Campus, Adelaide University, Woodville Sth, South Australia, Australia
    Search for more papers by this author
  • Jonathan Golledge

    1. The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia
    2. Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, QLD, Australia
    Search for more papers by this author

Abstract

Tenascin-C (Tn-C) is an endogenous ligand of toll-like receptor-4 (TLR-4); a key signalling molecule associated with chronic inflammatory conditions. Both Tn-C and TLR-4 are increased in unstable human atheroma, but their effects on local inflammatory conditions have not been investigated. The aim of the present study was to investigate the association and functional implications of Tn-C/TLR-4 signalling in large artery atherosclerotic stroke. Plasma Tn-C was measured by ELISA and found to be higher in recent stroke patients (n = 336; median 12.77 µg/mL, inter-quartile range 10.23–15.74 µg/mL) than in controls (n = 321; median 11.31 µg/mL, inter-quartile range 8.89–13.90 µg/mL), P < 0.001. Plasma Tn-C was also independently positively associated with stroke (odds ratio for highest Tn-C quartile 2.27, 95% confidence interval 1.37–3.76). Assessment of Tn-C associated chronic cytokine secretion was performed in vitro using paired, human, macroscopically disease matched, carotid atheroma tissue biopsies obtained from five patients undergoing carotid endarterectomy. A 4-day incubation with specific Tn-C blocking antibodies (Abs) increased secretion of TLR-4-associated cytokines, interleukin (IL)-8, IL-1β, tumour necrosis factor and C-C motif chemokine (CCL)3 and expression of TLR-4 in the tissue. These results suggest with Tn-C blockade another endogenous TLR-4 ligand upregulates TLR-4 expression and subsequent cytokine secretion. Titration of the Tn-C Abs also dose dependently increased secretion of IL-6, IL-8, IL-1β, and CCL3 in mixed, healthy, primary vascular cell culture. In summary, circulating concentrations of Tn-C are higher in patients with a recent history of atherosclerotic stroke and may play an anti-inflammatory role by reducing pro-inflammatory cytokine release from atheroma. © 2014 BioFactors, 40(4):448–457, 2014

Ancillary