Abstract 11803: Therapeutic Potential of Interleukine-37 for Suppression of Aortic Valve Inflammatory and Osteogenic Responses
The inflammatory and osteogenic responses of aortic valve interstitial cells (AVICs) play an important role in the progression of calcific aortic valve disease. An imbalance of the pro- and anti-inflammatory mechanisms may exaggerate the inflammatory and osteogenic responses in AVICs of diseased valves. Interleukine-37 (IL-37) is a novel anti-inflammatory cytokine expressed by human cells. It is unknown whether IL-37 expression is altered in AVICs of diseased human aortic valves and whether IL-37 suppresses the inflammatory and osteogenic responses in human AVICs. This study tested the hypothesis that IL-37 peptide could suppress aortic valve inflammatory and osteogenic responses in vitro and in vivo.
Methods and results: Analysis of cellular IL-37 levels revealed significant lower levels in AVICs of diseased human aortic valves in comparison to AVICs of normal human aortic valves. Treatment of AVICs of diseased valves with IL-37 peptide markedly reduced the production of intercellular adhesion molecule-1, bone morphogenetic protein-2 and alkaline phosphatase following stimulation with Toll-like receptor (TLR) 2/4 agonists. Conversely, silencing IL-37 in normal AVICs augmented the production of inflammatory and osteogenic mediators in response to stimulation of TLR2 or TLR4. Treatment of human AVICs with IL-37 peptide or expression of human IL-37 in mouse AVICs suppressed NF-κB activation induced by TLR2/4 stimulation. More importantly, expression of human IL-37 or treatment with human IL-37 peptide reduced aortic valve thickness in a murine model of aortic valve lesions.
Conclusions: IL-37 deficiency contributes to the mechanism underlying the exaggerated inflammatory and osteogenic responses in AVICs of diseased human aortic valves. IL-37 suppresses AVIC inflammatory and osteogenic responses through modulation of NF-κB activation, and could alleviate aortic valve lesions in vivo. The results of this study support the notion that an imbalance of the pro- and anti-inflammatory mechanisms in AVICs promotes the progression of calcific aortic valve disease and indicate that IL-37 may have a therapeutic potential for prevention of the progression of this disease.
- © 2012 by American Heart Association, Inc.