title: An endogenously anti-inflammatory role for methylation in mucosal inflammation identified through metabolite profiling.
abstract: Tissues of the mucosa are lined by an epithelium that provides barrier and transport functions. It is now appreciated that inflammatory responses in inflammatory bowel diseases are accompanied by striking shifts in tissue metabolism. In this paper, we examined global metabolic consequences of mucosal inflammation using both in vitro and in vivo models of disease. Initial analysis of the metabolic signature elicited by inflammation in epithelial models and in colonic tissue isolated from murine colitis demonstrated that levels of specific metabolites associated with cellular methylation reactions are significantly altered by model inflammatory systems. Furthermore, expression of enzymes central to all cellular methylation, S-adenosylmethionine synthetase and S-adenosylhomocysteine hydrolase, are increased in response to inflammation. Subsequent studies showed that DNA methylation is substantially increased during inflammation and that epithelial NF-κB activity is significantly inhibited following treatment with a reversible S-adenosylhomocysteine hydrolase inhibitor, DZ2002. Finally, these studies demonstrated that inhibition of cellular methylation in a murine model of colitis results in disease exacerbation while folate supplementation to promote methylation partially ameliorates the severity of murine colitis. Taken together, these results identify a global change in methylation, which during inflammation, translates to an overall protective role in mucosal epithelia.
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, University of Colorado Health Science Center, Aurora, CO 80045, USA. Douglas.Kominsky@ucdenver.edu
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kominsky
authors.forename: Simon
authors.initials: S
authors.lastname: Keely
authors.forename: Christopher F
authors.initials: CF
authors.lastname: MacManus
authors.forename: Louise E
authors.initials: LE
authors.lastname: Glover
authors.forename: Melanie
authors.initials: M
authors.lastname: Scully
authors.forename: Colm B
authors.initials: CB
authors.lastname: Collins
authors.forename: Brittelle E
authors.initials: BE
authors.lastname: Bowers
authors.forename: Eric L
authors.initials: EL
authors.lastname: Campbell
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D043383:Adenosylhomocysteinase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology; D045744:Cell Line, Tumor; D003092:Colitis / Q000235:genetics / Q000378:metabolism*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation / Q000187:drug effects; D016264:Dextran Sulfate / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D055432:Metabolomics / Q000379:methods*; D008716:Methionine Adenosyltransferase / Q000235:genetics / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D052016:Mucositis / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002087:Butyrates; D016328:NF-kappa B; C509291:methyl 4-(adenin-9-yl)-2-hydroxybutanoate; D007371:Interferon-gamma; D016264:Dextran Sulfate; D008716:Methionine Adenosyltransferase; D043383:Adenosylhomocysteinase; D000225:Adenine