Pycnogenol, an extract from French maritime pine, suppresses Toll-like receptor 4-mediated expression of adipose differentiation-related protein in macrophages.
Adipose differentiation-related protein (ADRP) is highly expressed in macrophages and human atherosclerotic lesions. We demonstrated that Toll-like receptor (TLR) 4-mediated signals, which are involved in atherosclerosis formation, enhanced the expression of ADRP in macrophages. Lipopolysaccharide (LPS) enhanced the ADRP expression in RAW264.7 cells or peritoneal macrophages from wild-type mice, but not in macrophages from TLR4-deficient mice. Actinomycin D almost completely abolished the LPS effect, whereas cycloheximide decreased the expression at 12 h, indicating that the LPS-induced ADRP expression was stimulated at the transcriptional level and was also mediated by new protein synthesis. LPS enhanced the ADRP promoter activity, in part, by stimulating activator protein (AP)-1 binding to the Ets/AP-1 element. In addition, preceding the increase of the ADRP mRNA, LPS induced the expression of interleukin (IL)-6, IL-1alpha, and interferon-beta mRNAs, all of which stimulated the ADRP expression. Antibodies against these cytokines or inhibitors of c-Jun NH(2)-terminal kinase and nuclear factor (NF)-kappaB suppressed the ADRP mRNA level. Thus TLR4 signals stimulate the ADRP expression both in direct and indirect manners. Pycnogenol (PYC), an extract of French maritime pine, suppressed the expression of ADRP and the above-mentioned cytokines. PYC suppressed the ADRP promoter activity and enhancer activity of AP-1 and NF-kappaB, whereas it did not affect the LPS-induced DNA binding of these factors. In conclusion, TLR4-mediated signals stimulate the ADRP expression in macrophages while PYC antagonizes this process. PYC, a widely used dietary supplement, might be useful for prevention of atherosclerosis.
Gu
Jian-Qiu
JQ
Dept. of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu Univ., Beppu 874-0838, Japan.
Ikuyama
Shoichiro
S
Wei
Ping
P
Fan
Bin
B
Oyama
Jun-Ichi
J
Inoguchi
Toyoshi
T
Nishimura
Junji
J
D000818:Animals; D002478:Cells, Cultured; D005419:Flavonoids / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D000070780:Perilipin-2; D028223:Pinus / Q000737:chemistry; D010936:Plant Extracts / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology
D005419:Flavonoids; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C000602982:PLIN2 protein, human; D000070780:Perilipin-2; D010936:Plant Extracts; C000602983:Plin2 protein, mouse; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C024070:pycnogenols