(American Journal of Pathology. 2005;166:1029-1039.)
© 2005 American Society for Investigative Pathology
Transforming Growth Factor-ß and Platelet-Derived Growth Factor Signal via c-Jun N-Terminal Kinase-Dependent Smad2/3 Phosphorylation in Rat Hepatic Stellate Cells after Acute Liver Injury
Katsunori Yoshida*,
Koichi Matsuzaki*,
Shigeo Mori*,
Yoshiya Tahashi*,
Hideo Yamagata*,
Fukiko Furukawa*,
Toshihito Seki*,
Mikio Nishizawa
,
Junichi Fujisawa
and
Kazuichi Okazaki*
From the Third Department of Internal Medicine* and the Departments of Medical Chemistry and Microbiology, Kansai Medical University, Osaka, Japan
After liver injury, transforming growth factor-ß (TGF-ß) and platelet-derived growth factor (PDGF) regulate the activation of hepatic stellate cells (HSCs) and tissue remodeling. Mechanisms of PDGF signaling in the TGF-ß-triggered cascade are not completely understood. TGF-ß signaling involves phosphorylation of Smad2 and Smad3 at linker and C-terminal regions. Using antibodies to distinguish Smad2/3 phosphorylated at linker regions from those phosphorylated at C-terminal regions, we investigated Smad2/3-mediated signaling in rat liver injured by CCl4 administration and in cultured HSCs. In acute liver injury, Smad2/3 were transiently phosphorylated at both regions. Although linker-phosphorylated Smad2 remained in the cytoplasm of 
-smooth muscle actin-immunoreactive mesenchymal cells adjacent to necrotic hepatocytes in centrilobular areas, linker-phosphorylated Smad3 accumulated in the nuclei. c-Jun N-terminal kinase (JNK) in the activated HSCs directly phosphorylated Smad2/3 at linker regions. Co-treatment of primary cultured HSCs with TGF-ß and PDGF activated the JNK pathway, subsequently inducing endogenous linker phosphorylation of Smad2/3. The JNK pathway may be involved in migration of resident HSCs within the space of Disse to the sites of tissue damage because the JNK inhibitor SP600125 inhibited HSC migration induced by TGF-ß and PDGF signals. Moreover, treatment of HSCs with both TGF-ß and PDGF increased transcriptional activity of plasminogen activator inhibitor-1 through linker phosphorylation of Smad3. In conclusion, TGF-ß and PDGF activate HSCs by transmitting their signals through JNK-mediated Smad2/3 phosphorylation at linker regions, both in vivo and in vitro.
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Copyright © 2005 by the American Society for Investigative Pathology.
