Ox-LDL-induced TGF-β1 production in human alveolar epithelial cells: involvement of the Ras/ERK/PLTP pathway.
Oxidized-low density lipoprotein (Ox-LDL) has been shown to play an important role in impaired surfactant metabolism and transforming growth factor-β1 (TGF-β1) is a critical mediator in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). In this study, we investigated whether Ox-LDL can induce TGF-β1 protein production, and if so, how it achieves this induction in human alveolar epithelial cells (A549). We show here that Ox-LDL not only caused a dose- and time-dependent up-regulation of TGF-β1 production, but also increased Smad3 phosphorylation, Ras/extracellular signal-regulated kinase (ERK) activity and phospholipid transfer protein (PLTP) expression in A549 cells. The inhibition of Ras/ERK activity with specific inhibitors significantly suppressed Ox-LDL-induced TGF-β1 production, Smad3 phosphorylation and PLTP expression. Furthermore, treatment of cells with PLTP siRNA suppressed both TGF-β1 release and Smad3 activation induced by Ox-LDL, but not the activation of Ras/ERK cascade. Taken together, we provide evidences that induction of TGF-β1 production and Smad3 phosphorylation by Ox-LDL is mediated by Ras/ERK/PLTP pathway in human alveolar epithelial cells.
Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China and Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
Ling-Li
LL
Guo
Ya-Juan
YJ
Chen
Tao
T
Wang
Jing
J
An
Cheng-Na
CN
Wang
Yong-Chun
YC
Shen
Ting
T
Yang
Li
L
Zhao
Qiu-Nan
QN
Zuo
Xiao-Hong
XH
Zhang
Dan
D
Xu
Fu-Qiang
FQ
Wen
D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D048748:MAP Kinase Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008798:Mevalonic Acid / Q000494:pharmacology; D049294:Phospholipid Transfer Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism; D034741:RNA, Small Interfering; D012128:Respiratory Distress Syndrome / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
D000960:Hypolipidemic Agents; D008077:Lipoproteins, LDL; C493430:PLTP protein, human; D049294:Phospholipid Transfer Proteins; D034741:RNA, Small Interfering; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C099252:oxidized low density lipoprotein; D019821:Simvastatin; D048748:MAP Kinase Kinase Kinase 3; D008798:Mevalonic Acid