Abstract：
:The interrelated signaling via TGF-beta1 and reactive oxygen species has a profound impact on fibrogenesis and is therefore selected as target for antifibrotic therapies. This prompted us to investigate the influence of the antioxidant N-acetyl-L-cysteine on TGF-beta signaling in culture-activated hepatic stellate cells, the most relevant pro-fibrogenic cell type in liver. Dissection of the molecular steps involved in TGF-beta signaling revealed that N-acetyl-L-cysteine dose-dependently abrogated the induction of the TGF-beta1 signaling reporter gene activation, the phosphorylation of Smad2 and Smad3, and the up-regulation of Smad7 mRNA. By means of Western blot analysis and cross-linking experiments, it was demonstrated that these effects are based on disintegration of TGF-beta1 and the TGF-beta receptor endoglin, as well as a reduced ligand binding capacity of betaglycan. We conclude that N-acetyl-L-cysteine is a specific inhibitor of TGF-beta signaling targeting different components of the TGF-beta signaling machinery. In conclusion, these findings suggest that this non-toxic aminothiol downregulates TGF-beta signal transduction thereby mediating beneficial effects on experimental liver fibrosis characterized by TGF-beta hyperactivity.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Meurer SK,Lahme B,Tihaa L,Weiskirchen R,Gressner AMdoi
10.1016/j.bcp.2005.07.001subject
Has Abstractpub_date
2005-10-01 00:00:00pages
1026-34issue
7eissn
0006-2952issn
1873-2968pii
S0006-2952(05)00452-1journal_volume
70pub_type
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