Adrenomedullin regulates expressions of transforming growth factor-beta1 and beta1-induced matrix metalloproteinase-2 in hepatic stellate cells.
Adrenomedullin (AM), a peptide isolated from human pheochromocytoma, can be produced and secreted by various types of cells including hepatic stellate cells (HSCs), and its possible role in HSCs is not clear now. In the present study, the interactive regulation between transforming growth factor (TGF)-beta1 and AM and the effect of AM on TGF-beta1-induced matrix metalloproteinase (MMP)-2 expression in HSCs were investigated. TGF-beta1 and AM inhibited gene transcript level mutually (real-time reverse transcription-polymerase chain reaction). AM suppressed the protein expression level of TGF-beta1 (Western blot), but TGF-beta1 might have no effect on AM secretion level. MMP-2 protein expression in HSCs was increased in response to TGF-beta1, and upregulation of MMP-2 expression stimulated with TGF-beta1 was suppressed by AM in dose-dependent manner (Western blot). AM decreased the phosphorylation level of extracellular signal-regulated kinase (ERK) in HSCs treated with TGF-beta1, and TGF-beta1-induced MMP-2 expression was suppressed by adding Mitogen-activated protein Kinase/ERK (MEK) inhibitor U(0126) (Western blot)(.) Our results suggest that AM may intervene the activation of HSCs by inhibiting TGF-beta1 production and TGF-beta1-induced MMP-2 expression; AM may suppress the upregulation of MMP-2 expression induced by TGF-beta1 partially through ERK pathway.
Wang
Yi
Y
Department of Pathology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Zhang
Jin-Sheng
JS
Qian
Jin
J
Huang
Guang-Cun
GC
Chen
Qi
Q
D053607:Adrenomedullin; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002461:Cell Line, Transformed; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D025461:Feedback, Physiological; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000032:analysis; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
D010455:Peptides; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053607:Adrenomedullin; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4; D020778:Matrix Metalloproteinase 2