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Mast cell‐mediated apoptosis of endothelial cells in vitro: A paracrine mechanism involving TNF‐α‐mediated down‐regulation of bcl‐2 expression
Author(s) -
Lätti Soili,
Leskinen Markus,
Shiota Naotaka,
Wang Yenfeng,
Kovanen Petri T.,
Lindstedt Ken A.
Publication year - 2003
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.10235
Subject(s) - paracrine signalling , microbiology and biotechnology , apoptosis , mechanism (biology) , autocrine signalling , in vitro , mast cell , chemistry , tumor necrosis factor alpha , biology , immunology , receptor , biochemistry , philosophy , epistemology
Abstract Degranulated mast cells are present in the subendothelial space of eroded (de‐endothelialized) coronary atheromas. Upon degranulation, mast cells secrete into the surrounding tissue an array of preformed and newly synthesized mediators, including proapoptotic molecules, such as chymase and TNF‐α. In a co‐culture system involving rat serosal mast cells and rat cardiac (microvascular) endothelial cells, we could show, by means of competitive RT‐PCR, immunoblotting, immunocytochemistry, annexin staining, flow cytometry, and DNA‐laddering, that stimulation of mast cells with ensuing degranulation rapidly (within 30 min) down‐regulated the expression of both bcl‐2 mRNA and protein, with subsequent induction of apoptosis in the endothelial cells. The major effect of bcl‐2 down‐regulation resided in the exocytosed granule remnants, a minor effect also being present in the granule remnant‐free supernatant. No significant changes were observed in the expression levels of the pro‐apoptotic protein, bax. The mast cell‐mediated apoptotic effect was partially (70%) dependent on the presence of TNF‐α and involved the translocation of cytochrome C from mitochondria into cytoplasm. These results are the first to show that one of the cell types present in the atherosclerotic plaques, namely the mast cell, by releasing both granule‐remnant‐bound and soluble TNF‐α, may contribute to the erosion of atherosclerotic plaques by inducing apoptosis in adjacent endothelial cells. Published 2003 Wiley‐Liss, Inc.