Published online before print December 6, 2001, doi: 10.1161/hh0102.102978
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© 2002 American Heart Association, Inc.
Molecular Medicine |
Secretory Phospholipase A2 Elicits Proinflammatory Changes and Upregulates the Surface Expression of Fas Ligand in Monocytic Cells
Potential Relevance for Atherogenesis
From the Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Facultad de Medicina; Instituto de Ciencias del Corazón (L.F., F.J.F.A., M.L.N.), Hospital Clínico Universitario, Valladolid, Spain.
Correspondence to Dr M. Sánchez Crespo, Instituto de Biología y Genética Molecular, Facultad de Medicina, 47005-Valladolid, Spain. E-mail mscres{at}ibgm.uva.es
Type IIA secretory phospholipase A2 (sPLA2) is an acute-phase reactant that plays a role in atherogenesis and is expressed in atherosclerotic arterial walls displaying inflammatory features. This generates a relevant question addressing the biological effects of this enzyme on monocytic cells, in view of the role of these cells in the inflammatory process associated with atherosclerosis. sPLA2 produced a mild activation of the p42 mitogen-activated protein module of the mitogen-activated protein kinase (MAPK) cascade and a prominent activation of c-Jun N-terminal kinase in THP-1 monocytes. This activation showed both an early and a late peak, different from that elicited by tumor necrosis factor-
(TNF-), which only showed the first peak. This was accompanied by activation of arachidonate metabolism, as judged from both the activation of the cytosolic phospholipase A2 (cPLA2) and the induction of cyclooxygenase-2 (COX-2) expression. sPLA2 also elicited the production of monocyte chemoattractant protein-1 (MCP-1) and showed a synergistic effect with TNF- on both COX-2 induction and MCP-1 production. sPLA2 upregulated the expression of Fas ligand at the cell surface, but it did not influence Fas expression nor cell survival of monocytes. In summary, these data indicate that some of the atherogenic effects of sPLA2 can be exerted by engagement of an sPLA2-binding structure on monocytic cells, most probably the M-type receptor for sPLA2, which produces the activation of the MAPK cascade, induces a proinflammatory phenotype, and upregulates the cell surface expression of Fas ligand.
Key Words: apoptosis • atherosclerosis • chemokines • inflammation • lipid mediators
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