Molecular inhibition of histone deacetylation results in major enhancement of the production of IL-1beta in response to LPS

• Published in: American journal of physiology: endocrinology and metabolism 2006-03, Vol.290 (3), p.E490-E493
• Main Authors: Sato, Timothy A, Mitchell, Murray D
• Format: Article
• Language: English
• Subjects: Acetylation - drug effects; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Decidua - drug effects; Decidua - metabolism; DNA Methylation; Enzyme Inhibitors - pharmacology; Female; Histones - antagonists & inhibitors; Histones - metabolism; Humans; Hydroxamic Acids - pharmacology; In Vitro Techniques; Interleukin-1 - biosynthesis; Interleukin-10 - biosynthesis; Pregnancy; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00406.2005

1 Liggins Institute, University of Auckland; and 2 National Research Centre for Growth and Development, Auckland, New Zealand Submitted 26 August 2005 ; accepted in final form 12 October 2005 It has been postulated that the progression of human pregnancy to term is, in part, the result of a relative maternal Th 2 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-1 receptor antagonist). 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 upregulation of IL-1 is known to be a causative factor. interleukin-1 ; lipopolysaccharide; histane deacetylation; human pregnancy Address for reprint requests and other correspondence: M. D. Mitchell, Liggins Institute, Faculty of Medical and Health Sciences, Univ. of Auckland, Private Bag 92019, Auckland, New Zealand (e-mail: m.mitchell{at}auckland.ac.nz )