Adrenomedullin regulates expressions of transforming growth factor-beta1 and beta1-induced matrix metalloproteinase-2 in hepatic stellate cells.

ABSTRACT

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.