N-acetyl-L-cysteine suppresses TGF-beta signaling at distinct molecular steps: the biochemical and biological efficacy of a multifunctional, antifibrotic drug.
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.
Meurer
Steffen K
SK
Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, Pauwelsstr. 30, D-52074 Aachen, Germany.
Lahme
Birgit
B
Tihaa
Lidia
L
Weiskirchen
Ralf
R
Gressner
Axel M
AM
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D008103:Liver Cirrhosis / Q000517:prevention & control*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D051906:Smad7 Protein; D015534:Trans-Activators / Q000037:antagonists & inhibitors; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004268:DNA-Binding Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D051906:Smad7 Protein; C497808:Smad7 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000111:Acetylcysteine