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: 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
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 186 Issue 11 Pg. 6505-14 (Jun 01 2011) ISSN: 1550-6606 [Electronic] United States
• PMID: 21515785 (Publication Type: Journal Article)

Chemical References

• Butyrates
• NF-kappa B
• methyl 4-(adenin-9-yl)-2-hydroxybutanoate
• Interferon-gamma
• Dextran Sulfate
• Methionine Adenosyltransferase
• Adenosylhomocysteinase
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology)
• Adenosylhomocysteinase (genetics, metabolism)
• Animals
• Blotting, Western
• Butyrates (pharmacology)
• Cell Line, Tumor
• Colitis (genetics, metabolism)
• Colon (drug effects, metabolism, pathology)
• DNA Methylation (drug effects)
• Dextran Sulfate (pharmacology)
• Epithelial Cells (drug effects, metabolism)
• Gene Expression Profiling (methods)
• HeLa Cells
• Humans
• Inflammation (genetics, metabolism)
• Interferon-gamma (metabolism, pharmacology)
• Intestinal Mucosa (metabolism, pathology)
• Magnetic Resonance Spectroscopy
• Metabolomics (methods)
• Methionine Adenosyltransferase (genetics, metabolism)
• Methylation (drug effects)
• Mice
• Mice, Inbred C57BL
• Mucositis (genetics, metabolism)
• NF-kappa B (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction