Molecular inhibition of histone deacetylation results in major enhancement of the production of IL-1beta in response to LPS.
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-1beta. The inhibition of histone deacetylation had no effect on LPS-stimulated TNF-alpha 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-alpha but not that of IL-1beta. The differential response is unique, and the relative uncoupling of IL-1beta and TNF-alpha responsiveness may have importance in other biological systems and provide new therapeutic targets for pathologies where upregulation of IL-1beta is known to be a causative factor.
Sato
Timothy A
TA
Liggins Institute, Faculty of Medical and Health Sciences, Univ. of Auckland, Private Bag 92019, Auckland, New Zealand. m.mitchell@auckland.ac.nz).
Mitchell
Murray D
MD
D000107:Acetylation / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019175:DNA Methylation; D003656:Decidua / Q000187:drug effects / Q000378:metabolism*; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006657:Histones / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis; D011247:Pregnancy; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D004791:Enzyme Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C012589:trichostatin A; D000077209:Decitabine; D001374:Azacitidine