Fas/FADD-induced pro-inflammatory response in vascular smooth muscle cells

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Fas/FADD-induced pro-inflammatory response in vascular smooth muscle cells

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Title: Fas/FADD-induced pro-inflammatory response in vascular smooth muscle cells
Author: Schaub, Friedemann
Abstract: Apoptosis of smooth muscle cells is a common feature of vascular lesions. Unlike necrosis, apoptosis is classically considered to be "silent," i.e., self-contained and non-inflammatory. I have found that signals initiated by Fas-associated death domain protein (FADD) overexpression in rat vascular smooth muscle cells in the carotid artery induce expression of monocyte-chemoattractant protein-1 (MCP-1) and Interleukin-8 (IL-8), and result in massive immigration of macrophages in vivo. These chemokines, and a specific subset of proinflammatory genes, are also upregulated in human vascular smooth muscle cells after treatment with Fas ligand (FasL) plus cycloheximide (Chx). I have determined that Fas/FADD-induced MCP-1 upregulation is regulated by increased synthesis and release of IL-1alpha and does not occur in cells derived from IL-1-receptor deficient mice. Inhibition of caspases and apoptosis only partly reduces gene induction in response to Fas/FADD activation. Calpain activation and cell death are the only known mechanisms through which IL-1alpha can be released. Calpain inhibitors effectively reduce Fas/FADD-mediated synthesis and release of IL-1alpha and consequently MCP-1 upregulation. My data provides strong evidence for a non-apoptosic Fas/FADD-activated signaling pathway, which involves activation of caspases, calpain and IL-1alpha signaling, leading to the induction of a program of pro-inflammatory gene expression. An important pathophysiological consequence of this pathway could be that the secreted IL-1alpha acts on healthy neighboring cells to amplify the pro-inflammatory signal and prolong it beyond the life time of the cells initially stimulated by Fas/FADD.
Description: Thesis (Ph. D.)--University of Washington, 2002
URI: http://hdl.handle.net/1773/6345

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