Tumor Necrosis Factor Alpha and Interleukin 1 Beta Suppress Myofibroblast Activation Via Nuclear Factor Kappa B Signaling in 3D-Cultured Mitral Valve Interstitial Cells

Abstract

Mitral valve disease is a major cause of cardiovascular morbidity throughout the world. Many different mitral valve pathologies demonstrate a pronounced degree of fibrotic remodeling, often accompanied by an inflammatory state. Mitral valve fibrosis is mediated by valvular interstitial cells (VICs), which reside in the valve leaflets and show a tendency to differentiate into myofibroblast-like cells during disease conditions. In this study, we investigated the effects of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) on mitral VICs, since these pro-inflammatory cytokines have been shown to exert pleiotropic effects on various cell types in other fibrotic disorders. Using biomimetic three-dimensional culture systems, we demonstrated that TNF-α and IL-1β suppress myofibroblast differentiation in mitral VICs, as evidenced by gene and protein expression of alpha smooth muscle actin and smooth muscle 22 alpha. Addition of TNF-α and IL-1β also inhibited mitral VIC-mediated contraction of collagen gels. Furthermore, inhibition of NF-κB, which is downstream of TNF-α and IL-1β, reversed these effects. These results reveal targetable pathways that could enable the development of pharmaceutical treatments for alleviating fibrosis during mitral valve disease.