Regulation of cell growth by redox-mediated extracellular proteolysis of platelet-derived growth factor receptor beta.
Redox-regulated processes are important elements in various cellular functions. Reducing agents, such as N-acetyl-l-cysteine (NAC), are known to regulate signal transduction and cell growth through their radical scavenging action. However, recent studies have shown that reactive oxygen species are not always involved in ligand-stimulated intracellular signaling. Here, we report a novel mechanism by which NAC blocks platelet-derived growth factor (PDGF)-induced signaling pathways in hepatic stellate cells, a fibrogenic player in the liver. Unlike in vascular smooth muscle cells, we found that reducing agents, including NAC, triggered extracellular proteolysis of PDGF receptor-beta, leading to desensitization of hepatic stellate cells toward PDGF-BB. This effect was mediated by secreted mature cathepsin B. In addition, type II transforming growth factor-beta receptor was also down-regulated. Furthermore, these events seemed to cause a dramatic improvement of rat liver fibrosis. These results indicated that redox processes impact the cell's response to growth factors by regulating the turnover of growth factor receptors and that "redox therapy" is promising for fibrosis-related disease.
Okuyama
H
H
Department of Gastroenterological Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8397, Japan. yokuyama@f8.dion.ne.jp
Shimahara
Y
Y
Kawada
N
N
Seki
S
S
Kristensen
D B
DB
Yoshizato
K
K
Uyama
N
N
Yamaoka
Y
Y
D000818:Animals; D001652:Bile Ducts / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D002401:Cathepsin B / Q000378:metabolism; D002403:Cathepsins / Q000494:pharmacology; D002455:Cell Division; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005355:Fibrosis; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D010084:Oxidation-Reduction; D011233:Precipitin Tests; D011480:Protease Inhibitors / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
D011480:Protease Inhibitors; D006861:Hydrogen Peroxide; D020797:Receptor, Platelet-Derived Growth Factor beta; D002403:Cathepsins; D002401:Cathepsin B