Toll-like receptor 4 is up-regulated by mTOR activation during THP-1 macrophage foam cells formation.
Macrophage foam cells formation is the most important process in atherosclerotic plaque formation and development. Toll-like receptor 4 (TLR4) is one of the important innate immune sensors of endogenous damage signals and crucial for regulating inflammation. Growing evidence indicates that TLR4 plays a very important role in macrophage foam cells formation. However, the underlying mechanisms regulating TLR4 expression in macrophage are not fully understood. In this study, we induced THP-1 macrophage foam cells formation with oxidative modified low-density lipoprotein (ox-LDL). We observed that TLR4 mRNA and protein expression were markedly up-regulated, and the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream target p70S6K were promoted during foam cells formation. The mTOR inhibitor rapamycin blocked mTOR phosphorylation and inhibited TLR4 expression induced by ox-LDL. Silencing mTOR, rictor or raptor protein expression by small interfering RNA, also inhibited the up-regulation of TLR4 expression, respectively. Inhibition of mTOR with rapamycin reversed the down-regulation of cellular lipid efflux mediator ABCA1, which resulted from the activation of TLR4 by ligands. These data suggested that TRL4 expression was up-regulated by a mechanism dependent on mTOR signal pathway activation during THP-1 macrophage foam cells formation. Inhibition of ox-LDL induced mTOR activation reduced TLR4 expression, and improved the impaired lipid efflux.
Key laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Miao
M
Yu
Xiaomin
X
Kang
Hong
H
Xue
Hongchao
H
Yin
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005487:Foam Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015854:Up-Regulation
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C492571:RICTOR protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C463659:RPTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; D051197:Toll-Like Receptor 4; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases