Lipid alterations in experimental murine colitis: role of ceramide and imipramine for matrix metalloproteinase-1 expression.
BACKGROUND
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.


RESULTS
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-1beta in Caco-2-IEC and human intestinal fibroblasts.


CONCLUSIONS
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-1beta 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.
Department of Internal Medicine I, University Medical Center, Regensburg, Germany.
Jessica
J
Bauer
Gerhard
G
Liebisch
Claudia
C
Hofmann
Christian
C
Huy
Gerd
G
Schmitz
Florian
F
Obermeier
Jürgen
J
Bock
D000818:Animals; D018938:Caco-2 Cells; D002518:Ceramides / Q000378:metabolism*; D003092:Colitis / Q000473:pathology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007099:Imipramine / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D019041:L-Selectin / Q000096:biosynthesis / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry*; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D002518:Ceramides; D053583:Interleukin-1beta; D008055:Lipids; D008244:Lysophosphatidylcholines; D014409:Tumor Necrosis Factor-alpha; D019041:L-Selectin; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase; D020781:Matrix Metalloproteinase 1; D007099:Imipramine