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(Circulation Research. 2002;90:38.)
© 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

Marita Hernández, Lucía Fuentes, Francisco Javier Fernández Avilés, Mariano Sánchez Crespo, María Luisa Nieto

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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