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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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MMP-1 protein expression of Caco-2 IEC is induced by exogenous SMase.Cells were incubated with increasing doses of exogenous SMase. Concentration of active MMP-1 was determined in supernatants after 24h by ELISA. (*p<0.05, **p<0.01; n = 6)
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pone-0007197-g004: MMP-1 protein expression of Caco-2 IEC is induced by exogenous SMase.Cells were incubated with increasing doses of exogenous SMase. Concentration of active MMP-1 was determined in supernatants after 24h by ELISA. (*p<0.05, **p<0.01; n = 6)

Mentions: MMP-1 protein production upon generation of ceramide was confirmed by quantification of active MMP-1 by ELISA. Supernatants of Caco-2 cells were analysed 24h after incubation with exogenous SMase (Figure 4). Exogenous SMase led to a dose-dependent increase of MMP-1 with a 3.1-fold increase at concentrations as low as 0.005 U/ml and maximal increase at a concentration of 0.125 U/ml (Figure 4).


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)

MMP-1 protein expression of Caco-2 IEC is induced by exogenous SMase.Cells were incubated with increasing doses of exogenous SMase. Concentration of active MMP-1 was determined in supernatants after 24h by ELISA. (*p<0.05, **p<0.01; n = 6)
© Copyright Policy
Related In: Results  -  Collection

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

pone-0007197-g004: MMP-1 protein expression of Caco-2 IEC is induced by exogenous SMase.Cells were incubated with increasing doses of exogenous SMase. Concentration of active MMP-1 was determined in supernatants after 24h by ELISA. (*p<0.05, **p<0.01; n = 6)
Mentions: MMP-1 protein production upon generation of ceramide was confirmed by quantification of active MMP-1 by ELISA. Supernatants of Caco-2 cells were analysed 24h after incubation with exogenous SMase (Figure 4). Exogenous SMase led to a dose-dependent increase of MMP-1 with a 3.1-fold increase at concentrations as low as 0.005 U/ml and maximal increase at a concentration of 0.125 U/ml (Figure 4).

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