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

Bauer J, Liebisch G, Hofmann C, Huy C, Schmitz G, Obermeier F, Bock J - PLoS ONE (2009)

Bottom Line: Lysophosphatidylcholine (LPC) decreased by 22% in both models.Mucosal inflammation leads to accumulation of ceramide and decrease of LPC in the intestinal epithelium.Therefore, inhibition of ASM may offer a treatment strategy to reduce MMP-1 expression and tissue destruction in inflammatory conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine I, University Medical Center, Regensburg, Germany.

ABSTRACT

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.

Methodology/principal findings: 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/significance: 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.

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Induction of MMP-1- and MMP-10-mRNA in the intestinal epithelial cell line Caco-2 after generation of ceramide by exogenous SMase (0,1U/ml), as determined by affymetrix gene array analysis.Data are presented as relative increase after 6h and 24h in comparison to untreated control. (n = 4; ***p<0.001)
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pone-0007197-g003: Induction of MMP-1- and MMP-10-mRNA in the intestinal epithelial cell line Caco-2 after generation of ceramide by exogenous SMase (0,1U/ml), as determined by affymetrix gene array analysis.Data are presented as relative increase after 6h and 24h in comparison to untreated control. (n = 4; ***p<0.001)

Mentions: Based on the differences found in chronic colitis, we examined the effects of ceramide generation in IEC by affymetrix gene array analysis. Therefore the colorectal cancer cell line Caco-2 was incubated with exogenous SMase (0.1 U/ml) to identify ceramide induced effects possibly involved in IBD pathophysiology. The experiments revealed a fast and robust increase of MMP-1 and MMP-10 (Figure 3). The induction of MMP-10 was not further investigated.


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

Bauer J, Liebisch G, Hofmann C, Huy C, Schmitz G, Obermeier F, Bock J - PLoS ONE (2009)

Induction of MMP-1- and MMP-10-mRNA in the intestinal epithelial cell line Caco-2 after generation of ceramide by exogenous SMase (0,1U/ml), as determined by affymetrix gene array analysis.Data are presented as relative increase after 6h and 24h in comparison to untreated control. (n = 4; ***p<0.001)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2749204&req=5

pone-0007197-g003: Induction of MMP-1- and MMP-10-mRNA in the intestinal epithelial cell line Caco-2 after generation of ceramide by exogenous SMase (0,1U/ml), as determined by affymetrix gene array analysis.Data are presented as relative increase after 6h and 24h in comparison to untreated control. (n = 4; ***p<0.001)
Mentions: Based on the differences found in chronic colitis, we examined the effects of ceramide generation in IEC by affymetrix gene array analysis. Therefore the colorectal cancer cell line Caco-2 was incubated with exogenous SMase (0.1 U/ml) to identify ceramide induced effects possibly involved in IBD pathophysiology. The experiments revealed a fast and robust increase of MMP-1 and MMP-10 (Figure 3). The induction of MMP-10 was not further investigated.

Bottom Line: Lysophosphatidylcholine (LPC) decreased by 22% in both models.Mucosal inflammation leads to accumulation of ceramide and decrease of LPC in the intestinal epithelium.Therefore, inhibition of ASM may offer a treatment strategy to reduce MMP-1 expression and tissue destruction in inflammatory conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine I, University Medical Center, Regensburg, Germany.

ABSTRACT

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.

Methodology/principal findings: 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/significance: 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.

Show MeSH
Related in: MedlinePlus