Lipid Alterations in Experimental Murine Colitis: Role of Ceramide and Imipramine for Matrix Metalloproteinase-1 Expression
Open Access
- 29 September 2009
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 4 (9), e7197
- https://doi.org/10.1371/journal.pone.0007197
Abstract
Dietary lipids or pharmacologic modulation of lipid metabolism are potential therapeutic strategies in inflammatory bowel disease (IBD). Therefore, we analysed alterations of bioactive lipids in experimental models of colitis and examined the functional consequence of the second messenger ceramide in inflammatory pathways leading to tissue destruction. Chronic colitis was induced by dextran-sulphate-sodium (DSS) or transfer of CD4+CD62L+ cells into RAG1−/−-mice. Lipid content of isolated murine intestinal epithelial cells (IEC) was analysed by tandem mass spectrometry. Concentrations of MMP-1 in supernatants of Caco-2-IEC and human intestinal fibroblasts from patients with ulcerative colitis were determined by ELISA. Imipramine was used for pharmacologic inhibition of acid sphingomyelinase (ASM). Ceramide increased by 71% in chronic DSS–induced colitis and by 159% in the transfer model of colitis. Lysophosphatidylcholine (LPC) decreased by 22% in both models. No changes were detected for phosphatidylcholine. Generation of ceramide by exogenous SMase increased MMP-1-protein production of Caco-2-IEC up to 7-fold. Inhibition of ASM completely abolished the induction of MMP-1 by TNF or IL-1β in Caco-2-IEC and human intestinal fibroblasts. Mucosal inflammation leads to accumulation of ceramide and decrease of LPC in the intestinal epithelium. One aspect of ceramide generation is an increase of MMP-1. Induction of MMP-1 by TNF or IL-1β is completely blocked by inhibition of ASM with imipramine. Therefore, inhibition of ASM may offer a treatment strategy to reduce MMP-1 expression and tissue destruction in inflammatory conditions.Keywords
This publication has 56 references indexed in Scilit:
- Matrix metalloproteinase‐1 expression induced by IL‐1β requires acid sphingomyelinaseFEBS Letters, 2009
- The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of common diseasesThe FASEB Journal, 2008
- Nanomolar concentrations of lysophosphatidylcholine recruit monocytes and induce pro-inflammatory cytokine production in macrophagesBiochemical and Biophysical Research Communications, 2008
- Principles of bioactive lipid signalling: lessons from sphingolipidsNature Reviews Molecular Cell Biology, 2008
- The Role of Matrix Metalloproteinases in Stromal/Epithelial Interactions in the GutPhysiology, 2007
- Anti-inflammatory Effects of PhosphatidylcholineJournal of Biological Chemistry, 2007
- Acid sphingomyelinase inhibition suppresses lipopolysaccharide‐mediated release of inflammatory cytokines from macrophages and protects against disease pathology in dextran sulphate sodium‐induced colitis in miceImmunology, 2007
- Enhancement of Fibroblast Collagenase (Matrix Metalloproteinase-1)Gene Expression by Ceramide Is Mediated by Extracellular Signal-regulated and Stress-activated Protein Kinase PathwaysPublished by Elsevier BV ,1998
- Ceramide signalling and the immune responseBiochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1996
- Polyunsaturated phosphatidylcholine prevents stricture formation in a rat model of colitisGastroenterology, 1996