An endogenously anti-inflammatory role for methylation in mucosal inflammation identified through metabolite profiling

Douglas J. Kominsky, Simon Keely, Christopher F. MacManus, Louise E. Glover, Melanie Scully, Colm B. Collins, Brittelle E. Bowers, Eric L. Campbell, Sean P. Colgan

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)6505-6514
Number of pages10
JournalJournal of Immunology
Volume186
Issue number11
DOIs
Publication statusPublished - 01 Jun 2011
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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