Platelet-activating factor and oxidized LDL induce immune activation by a common mechanism.
Platelet activating factor (PAF) is a phospholipid with proinflammatory and thrombogenic properties, which has been implicated in inflammatory disorders including vasculitis and asthma. PAF-like compounds are present in oxidized LDL (oxLDL), which has been detected in the atherosclerotic lesion, where it may activate monocytes, macrophages, and T cells. OxLDL may therefore both initiate and perpetuate inflammatory reactions in the artery wall. Herein we demonstrate that PAF has the capacity to induce enhanced interferon gamma (IFN-gamma) secretion in peripheral blood mononuclear leukocytes (PBMCs), as does oxLDL. Both oxLDL- and PAF-induced IFN-gamma secretions were inhibited by a specific PAF-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 histocompatibility complex class II and thus depend on accessory cells like monocytes. Both PAF and oxLDL induced tumor necrosis factor-alpha (TNF-alpha) synthesis in peripheral blood. PAF-mediated TNF-alpha production was inhibited by WEB 2170, whereas oxLDL-induced TNF-alpha was only partially inhibited. These findings indicate that both PAF and oxLDL have the capacity to induce TNF-alpha, which may increase atherogenesis due to its pleiotropic proinflammatory effects. Our findings suggest that the PAF receptor plays an important role in the inflammatory component of atherosclerosis.
Frostegård
J
J
Department of Medicine, Karolinska Hospital, Stockholm, Sweden. johanf@rheum.ks.se
Huang
Y H
YH
Rönnelid
J
J
Schäfer-Elinder
L
L
D001381:Azepines / Q000494:pharmacology; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010972:Platelet Activating Factor / Q000031:analogs & derivatives / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001381:Azepines; D008077:Lipoproteins, LDL; C029271:O-deacetyl platelet activating factor; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; C039351:platelet activating factor receptor; D007371:Interferon-gamma; C063964:bepafant