Date of Award
Campus Access Dissertation
Heart diseases have been the number one health threat in the western world for decades. A common consequence of various heart diseases is the abnormal accumulation of extracellular matrix or cardiac fibrosis. Severe cardiac fibrosis alters the mechanical properties of the myocardium and is thought to contribute to the progression towards heart failure. Despite significant advances in our understanding of the fibrotic process, there is currently not an accepted remedy for this process. Cardiac fibroblasts are the cells primarily responsible for extracellular matrix homeostasis, thus rendering them as an attractive target for controlling cardiac fibrosis. Recent studies have suggested a clear role for inflammation in the modulation of cardiac fibrosis. Interleukin-33 (IL-33) is a comparatively new cytokine and that appears to have protective role in pressure-induced cardiac fibrosis. Many questions remain regarding the mechanisms of these protective effects and the effects that IL-33 has on cardiac fibroblasts or other cardiac cells. Based upon published literature, we hypothesized that IL-33 either directly or indirectly modulates expression of extracellular matrix components by cardiac fibroblasts. To test this hypothesis, we investigated the effects of IL-33 on cardiac fibroblast behavior (proliferation, migration, etc) and gene expression. As mast cells have been demonstrated to impact cardiac remodeling and fibrosis, we also investigated the effects of IL-33 on these cells. We discovered that cardiac fibroblasts express functional IL-33 receptors and IL-33 directly regulates cardiac fibroblast migration and cytokine expression in a dose-dependent manner. Moreover, these modulations were mediated via activation of mitogen-activated protein (MAP) kinase and NF-kB pathways. However, we did not observe any inhibition of extracellular matrix protein production by cardiac fibroblasts by treatment with IL-33. On the other hand, IL-33 treatment inhibited mast cell functions including proliferation and migration. Overall, the current studies provide important insight into the effects of IL-33 on myocardial cells. Based upon these studies, future in vitro and in vivo studies should be pursued to further evaluate the effects of IL-33 in myocardial remodeling and fibrosis.
ZHU, J.(2012). Role of Interleukin 33 In Modulating Cardiac Fibroblast and Mast Cell Gene Expression and Function. (Doctoral dissertation). Retrieved from http://scholarcommons.sc.edu/etd/2128