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. sPLA2produced 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-&agr; (TNF-&agr;), 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. sPLA2also elicited the production of monocyte chemoattractant protein-1 (MCP-1) and showed a synergistic effect with TNF-&agr; on both COX-2 induction and MCP-1 production. sPLA2upregulated 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 sPLA2can 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.