PLATELET-ACTIVATING-FACTOR AND OXIDIZED LDL INDUCE IMMUNE ACTIVATION BY A COMMON MECHANISM

Platelet activating factor (PAF) is a phospholipid with proinflammator y and thrombogenic properties, which has been implicated in inflammato ry disorders including vasculitis and asthma. PAF-like compounds are p resent in oxidized LDL (oxLDL), which has been detected in the atheros clerotic lesion, where it may activate monocytes, macrophages, and T c ells. OxLDL may therefore both initiate and perpetuate inflammatory re actions in the artery wall. Herein we demonstrate that PAF has the cap acity to induce enhanced interferon gamma (IFN-gamma) secretion in per ipheral blood mononuclear leukocytes (PBMCs), as does oxLDL. Both oxLD L- and PAF-induced IFN-gamma secretions were inhibited by a specific P AF-receptor antagonist, WEB 2170. PAF-like lipids in oxLDL could thus be responsible for oxLDL-induced activation of immune-competent cells. The effects of PAF and oxLDL were inhibited by antibodies to major hi stocompatibility complex class II and thus depend on accessory cells l ike monocytes. Both PAF and oxLDL induced tumor necrosis factor-alpha (TNF-alpha) synthesis in peripheral blood. PAF-mediated TNF-alpha prod uction was inhibited by WEB 2170, whereas oxLDL-induced TNF-alpha was only partially inhibited. These findings indicate that both PAF and ox LDL have the capacity to induce TNF-alpha, which may increase atheroge nesis due to its pleiotropic proinflammatory effects. Our findings sug gest that the PAF receptor plays an important role in the inflammatory component of atherosclerosis.