Submitted on August 26, 2005
Accepted on October 12, 2005
The Molecular Inhibition of Histone Deacetylation Results in Major Enhancement of the Production of Interleukin-1
in Response to Lipopolysaccharide
Timothy A Sato1 and Murray D Mitchell2*
1 Liggins Institute, University of Auckland, Auckland, New Zealand
2 Liggins Institute, University of Auckland, Auckland, New Zealand; National Research Centre for Growth and Development, University of Auckland, Auckland, New Zealand
* To whom correspondence should be addressed. E-mail: m.mitchell{at}auckland.ac.nz.
It has been postulated that the progression of human pregnancy to term is, in part, the result of a relative maternal Th2 immunological state. This can be activated in some cell types by modifying DNA methylation and histone acetylation status. We demonstrate that the molecular inhibition of histone deacetylation, using trichostatin A (TSA), in human choriodecidual explants leads to a massive increase in lipopolysaccharide (LPS)-stimulated IL-1
. The inhibition of histone deacetylation had no effect on LPS-stimulated TNF-
, production or production of the other cytokines studied (IL-10, IL-1Ra). The molecular inhibition of DNA methylation and histone deacetylation, using 5-aza-2' deoxycytidine and TSA, respectively, in human choriodecidual explants also results in an increase in the basal production of TNF-, but not that of IL-1. The differential response is unique and the relative uncoupling of IL-1 and TNF- responsiveness may have importance in other biological systems and provide new therapeutic targets for pathologies where up regulation of IL-1 is known to be a causative factor.
