title: Inhibition by deacetylase inhibitors of IL-1-dependent induction of haptoglobin involves CCAAT/Enhancer-binding protein isoforms in intestinal epithelial cells.
abstract: Intestinal epithelial cells participate in an acute phase response (APR) by responding to cytokines and by expressing acute phase protein genes. We hypothesized that butyrate, a fermentation product of the bacterial intestinal flora with deacetylase activity, affects the APR in intestinal epithelial cells. Sodium butyrate (NaBu) and Trichostatin A (TSA) induced alkaline phosphatase activity and histone H4 acetylation in IEC-6 rat intestinal epithelial cells treated with or without interleukin-1beta (IL-1). In contrast, both NaBu and TSA attenuated the IL-1-dependent induction of the acute phase protein gene haptoglobin, as well as C/EBPbeta and C/EBPdelta transcription factors mRNAs. Gel shift and supershift assays showed a strong decrease in the IL-1-induced C/EBPbeta and C/EBPdelta containing complexes binding to the HaptoA C/EBP DNA-binding site of the haptoglobin promoter, by NaBu and TSA. Furthermore, site-specific mutation of the HaptoA site abolished the NaBu- and TSA-dependent inhibition of haptoglobin, as determined by transient transfection assays. These results suggest that deacetylase inhibitors may regulate the IL-1 dependent induction of haptoglobin by down-regulating C/EBP isoforms, and that C/EBPs represent a target for the action of butyrate in the control of the APR of intestinal epithelial cells.
authors.affiliation: Groupe de recherche en biologie du développement, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Désilets
authors.forename: I
authors.initials: I
authors.lastname: Gheorghiu
authors.forename: S J
authors.initials: SJ
authors.lastname: Yu
authors.forename: E G
authors.initials: EG
authors.lastname: Seidman
authors.forename: C
authors.initials: C
authors.lastname: Asselin
mesh_terms: D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006242:Haptoglobins / Q000096:biosynthesis* / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D007375:Interleukin-1 / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology / Q000187:drug effects; D020033:Protein Isoforms / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats
chemical_list: D002087:Butyrates; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; D004791:Enzyme Inhibitors; D006242:Haptoglobins; D056572:Histone Deacetylase Inhibitors; D007375:Interleukin-1; D020033:Protein Isoforms; D012333:RNA, Messenger