کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2795034 | 1155308 | 2009 | 12 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Serum factors potentiate hypoxia-induced hepatotoxicity in vitro through increasing transforming growth factor-β1 activation and release
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
علوم غدد
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چکیده انگلیسی
Although transforming growth factor-β (TGF-β), a growth regulator of hepatocytes, induces cell death under pathological conditions, responsiveness of hepatocytes to hypoxic stimulus has not been fully defined. This study aimed at investigating the role of TGF-β1 in hypoxia-induced hepatotoxicity using cultured clone-9 hepatocytes with or without serum supplementation. Methods/Results: Presence of serum significantly potentiated hypoxia-induced hepatotoxicity after 72 h of exposure, as evidenced by fluorescent viability stain and LDH cytotoxicity assay. Quantitative PCR showed that TGF-β1 gene expression decreased, while ELISA revealed that latent TGF-β1 in conditioned media prominently increased in serum-treated groups under hypoxia. Western blotting indicated that both type I and II receptors of TGF-β were up-regulated in serum-free groups, but down-regulated in serum-treated groups under hypoxia. Smad2 phosphorylation was only detectable in cells supplemented with serum, and hypoxia potentiated the extent of Smad2 phosphorylation, implicating that the activated TGF-β1 induces hepatotoxicity in an autocrine manner. Addition of exogenous TGF-β1 deteriorated, while TGF-β1 blockade by neutralizing antibody ameliorated hypoxia-induced hepatotoxicity with serum supplementation. Gelatine zymography and immunofluorescent stain evidenced that elevated MMP-2 and MMP-9 activity and serum-dependent CD44 expression and its membranous localization may contribute to TGF-β1 activation. Conclusion: The results suggest that the mechanism governing TGF-β activation plays a crucial role in hypoxia-induced hepatotoxicity. Thus, interventions on TGF-β1 bioavailability and/or its cognate signaling may be of benefit in preventing hypoxia-related liver injuries.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cytokine - Volume 47, Issue 1, July 2009, Pages 11-22
Journal: Cytokine - Volume 47, Issue 1, July 2009, Pages 11-22
نویسندگان
Ying-Hsien Kao, Bruno Jawan, Shigeru Goto, Mei-Chun Pan, Yu-Chun Lin, Cheuk-Kwan Sun, Li-Wen Hsu, Ming-Hong Tai, Yu-Fan Cheng, Toshiaki Nakano, Chih-Shien Wang, Chia-Jung Huang, Chao-Long Chen,