Tenascin-C is increased in atherothrombotic stroke patients and has an anti-inflammatory effect in the human carotid artery.
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.
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.
Paula
P
Clancy
Lisa F
LF
Lincz
Jane
J
Maguire
Mark
M
McEvoy
Simon A
SA
Koblar
Jonathan
J
Golledge
D000368:Aged; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002340:Carotid Artery Diseases / Q000097:blood*; D002341:Carotid Artery Thrombosis / Q000097:blood*; D016022:Case-Control Studies; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D061251:Primary Cell Culture; D019063:Tenascin / Q000097:blood*; D046509:Tissue Culture Techniques; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D016207:Cytokines; D018836:Inflammation Mediators; C495345:TLR4 protein, human; D019063:Tenascin; D051197:Toll-Like Receptor 4
anti-inflammatory; atheroma; stroke; tenascin-C; toll-like receptor-4