Dualism of oxidized lipoproteins in provoking and attenuating the oxidative burst in macrophages: role of peroxisome proliferator-activated receptor-gamma.
Activation and deactivation of macrophages are of considerable importance during the development of various disease states, atherosclerosis among others. Macrophage activation is achieved by oxidized lipoproteins (oxLDL) and is determined by oxygen radical (ROS) formation. The oxidative burst was measured by flow cytometry and quantitated by oxidation of the redox-sensitive dye dichlorodihydrofluorescein diacetate. Short-time stimulation dose-dependently elicited ROS formation. Diphenylene iodonium prevented ROS formation, thus pointing to the involvement of a NAD(P)H oxidase in producing reduced oxygen species. In contrast, preincubation of macrophages with oxLDL for 16 h showed an attenuated oxidative burst upon a second contact with oxLDL. Taking into account that oxLDL is an established peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist and considering the anti-inflammatory properties of PPARgamma, we went on and showed that a PPARgamma agonist such as ciglitazone attenuated ROS formation. Along that line, major lipid peroxidation products of oxLDL, such as 9- and 13-hydroxyoctadecadienoic acid, shared that performance. Supporting evidence that PPARgamma activation accounted for reduced ROS generation came from studies in which proliferator-activated receptor response element decoy oligonucleotides, but not a mutated oligonucleotide, supplied in front of oxLDL delivery regained a complete oxidative burst upon cell activation. We conclude that oxLDL not only elicits an oxidative burst upon first contact, but also promotes desensitization of macrophages via activation of PPARgamma. Desensitization of macrophages may have important consequences for the behavior of macrophages/foam cells in atherosclerotic lesions.
Fischer
Barbara
B
Faculty of Biology, Department of Cell Biology, University of Kaiserslautern, Kaiserslautern, Germany.
von Knethen
Andreas
A
Brüne
Bernhard
B
D000818:Animals; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008041:Linoleic Acids / Q000494:pharmacology; D044243:Linoleic Acids, Conjugated; D008077:Lipoproteins, LDL / Q000494:pharmacology / Q000502:physiology*; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D016897:Respiratory Burst / Q000187:drug effects / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D020298:U937 Cells / Q000187:drug effects / Q000378:metabolism
D008041:Linoleic Acids; D044243:Linoleic Acids, Conjugated; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C099252:oxidized low density lipoprotein; C024347:9-hydroxy-10,12-octadecadienoic acid; C024348:13-hydroxy-9,11-octadecadienoic acid; C039671:ciglitazone