15d-PGJ2 inhibits oxidized LDL-induced macrophage proliferation by inhibition of GM-CSF production via inactivation of NF-kappaB.
Macrophage-derived foam cells play an important role in atherosclerotic lesions. Oxidized low-density lipoprotein (Ox-LDL) induces macrophage proliferation via production of GM-CSF in vitro. This study investigated the effects of 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a natural ligand for peroxisome proliferator-activated receptor gamma, on macrophage proliferation. Mouse peritoneal macrophages and RAW264.7 cells were used for proliferation study and reporter gene assay, respectively. Twenty microgram per milliliter of Ox-LDL induced [3H]thymidine incorporation in mouse peritoneal macrophages, and 15d-PGJ(2) inhibited Ox-LDL-induced [3H]thymidine incorporation in a dose-dependent manner. Ox-LDL increased GM-CSF release and GM-CSF mRNA expression, and activated GM-CSF gene promoter, all of which were prevented by 15d-PGJ(2) or 2-cyclopenten-1-one, a cyclopentenone ring of 15d-PGJ(2). The suppression of GM-CSF promoter activity by 15d-PGJ(2) and 2-cyclopenten-1-one was mediated through reduction of NF-kappaB binding to GM-CSF promoter. These results suggest that 15d-PGJ(2) inhibits Ox-LDL-induced macrophage proliferation through suppression of GM-CSF production via NF-kappaB inactivation.
Matsuo
Tomoko
T
Department of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Matsumura
Takeshi
T
Sakai
Masakazu
M
Senokuchi
Takafumi
T
Yano
Miyuki
M
Kiritoshi
Shinsuke
S
Sonoda
Kazuhiro
K
Kukidome
Daisuke
D
Pestell
Richard G
RG
Brownlee
Michael
M
Nishikawa
Takeshi
T
Araki
Eiichi
E
D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003517:Cyclopentanes / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013936:Thymidine / Q000031:analogs & derivatives / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
C477819:15-deoxyprostaglandin J2; D003517:Cyclopentanes; D008077:Lipoproteins, LDL; D016328:NF-kappa B; C099252:oxidized low density lipoprotein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004247:DNA; D008156:Luciferases; C013905:cyclopentenone; D015230:Prostaglandin D2; D013936:Thymidine