Journal
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
Volume 41, Issue 11, Pages 2270-2280Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2009.05.003
Keywords
Hypoxia; Transcriptional repression; MCP-1; Histone deacetylase; NF-kappa B
Categories
Funding
- Japan Society for the Promotion of Science [15.52341, 17.05243]
- Frontier Research on Molecular Destruction
- Reconstitution of Tooth and Bone.
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Hypoxia is a microenvironmental factor frequently associated with tumors and inflammation This study addresses the question of how hypoxia modulates the basal and IL-1 beta-incluced production of cytokines and aims to identify the underlying mechanism of hypoxic transcriptional repression. We found that despite the similarities of the promoter structures of IL-8 and MCP-1, these chemokines were differently regulated by hypoxia (an increase in IL-8, but a decrease in MCP-1 mRNA and protein expression). Such differences were not observed in a reporter gene assay, in which both of the promoters were activated by hypoxia. The difference in the response to hypoxia between MCP-1 expression and the promoter assay was not due to mRNA instability. Using proteosome inhibitor MG132 and I kappa B overexpresssion we demonstrated that an NF-kappa B-dependent mechanism was involved in both the activation of IL-8 and the repression of MCP-1 mRNA expression in response to hypoxia. The histone deacetylase inhibitor Trihostatin A abolished the inhibitory actions of hypoxia on IL-1 beta-induced MCP-1 gene expression. Furthermore, hypoxia induced histone deacetylase activity in the nuclear extracts. Although stimulation with IL-1 beta and/or hypoxia increased the acetylation of histories H3 and H4 in the presence of Trihostatin A, histone acetylation remained unchanged when the cells were treated without histone deacetylase inhibitor. Collectively, our findings suggest that transiently transfected promoters are not subject to the same NF-kappa B regulatory mechanisms as their chromatinized counterparts. NF-kappa B. activated by hypoxia, can act as a transcriptional repressor via a mechanism that involves deacetylation of histories. (C) 2009 Elsevier Ltd. All rights reserved.
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