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Serum factors potentiate hypoxia-induced hepatotoxicity in vitro through increasing transforming growth factor-β1 activation and release
- Source :
-
Cytokine . Jul2009, Vol. 47 Issue 1, p11-22. 12p. - Publication Year :
- 2009
-
Abstract
- Abstract: Background: 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 72h 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. [Copyright &y& Elsevier]
Details
- Language :
- English
- ISSN :
- 10434666
- Volume :
- 47
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Cytokine
- Publication Type :
- Academic Journal
- Accession number :
- 42100372
- Full Text :
- https://doi.org/10.1016/j.cyto.2009.03.004