Header

UZH-Logo

Maintenance Infos

Sphingomyelin induces cathepsin D-mediated apoptosis in intestinal epithelial cells and increases inflammation in DSS colitis.


Fischbeck, A; Leucht, K; Frey-Wagner, I; Bentz, S; Pesch, T; Kellermeier, S; Krebs, M; Fried, M; Rogler, G; Hausmann, M; Humpf, H U (2011). Sphingomyelin induces cathepsin D-mediated apoptosis in intestinal epithelial cells and increases inflammation in DSS colitis. Gut, 60(1):55-65.

Abstract

t

BACKGROUND: The sphingolipid sphingomyelin is a constituent in food derived from animals. Digestive breakdown of sphingomyelin results in ceramide, recently suggested to be involved in activation of cathepsin D as a novel mediator of apoptosis. Damage of the epithelial barrier was detected in patients with inflammatory bowel disease (IBD) due to increased rates of intestinal epithelial cell (IEC) apoptosis.

METHODS: Acute colitis was induced in C57-BL/6 mice with 2.0% dextran sulfate sodium (DSS) over 7 days. Spontaneous colitis was developed in B6-IL10tm1Cgn (interleukin 10-negative (IL-10(-/-))) mice. Mice received 4 or 8 mg sphingomyelin/day by oral gavage. IECs were isolated ex vivo. Apoptosis was determined by propidium iodide (PI) and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining. Execution of apoptosis was confirmed by analysis of active cathepsin D, caspase-3 and caspase-9 with western blot and immunohistochemistry (IHC).

RESULTS: Following DSS-mediated colitis, fluorescence-activated cell sorting (FACS) analysis indicated increased apoptosis of IECs under dietary sphingomyelin. The mean sub-G(1) portion increased from 8.7±2.5% under a normal diet to 14.0±3.1% under dietary sphingomyelin. Cathepsin activity was significantly increased in isolated IECs after gavage of 4 mg of sphingomyelin per day. Western blot and IHC revealed execution of the apoptotic cascade via activated caspase-3 and caspase-9. Dietary sphingomyelin in the IL-10(-/-) model confirmed aggravation of mucosal inflammation.

CONCLUSION: Apoptosis of IEC induced by dietary sphingomyelin is mediated via ceramide and cathepsin D activation. This shortens the physiological life cycle of IECs and impairs crucial functions of the intestinal mucosa: barrier, defence and nutrient absorption. The findings provide evidence that dietary sphingomyelin may increase intestinal inflammation.

Abstract

t

BACKGROUND: The sphingolipid sphingomyelin is a constituent in food derived from animals. Digestive breakdown of sphingomyelin results in ceramide, recently suggested to be involved in activation of cathepsin D as a novel mediator of apoptosis. Damage of the epithelial barrier was detected in patients with inflammatory bowel disease (IBD) due to increased rates of intestinal epithelial cell (IEC) apoptosis.

METHODS: Acute colitis was induced in C57-BL/6 mice with 2.0% dextran sulfate sodium (DSS) over 7 days. Spontaneous colitis was developed in B6-IL10tm1Cgn (interleukin 10-negative (IL-10(-/-))) mice. Mice received 4 or 8 mg sphingomyelin/day by oral gavage. IECs were isolated ex vivo. Apoptosis was determined by propidium iodide (PI) and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining. Execution of apoptosis was confirmed by analysis of active cathepsin D, caspase-3 and caspase-9 with western blot and immunohistochemistry (IHC).

RESULTS: Following DSS-mediated colitis, fluorescence-activated cell sorting (FACS) analysis indicated increased apoptosis of IECs under dietary sphingomyelin. The mean sub-G(1) portion increased from 8.7±2.5% under a normal diet to 14.0±3.1% under dietary sphingomyelin. Cathepsin activity was significantly increased in isolated IECs after gavage of 4 mg of sphingomyelin per day. Western blot and IHC revealed execution of the apoptotic cascade via activated caspase-3 and caspase-9. Dietary sphingomyelin in the IL-10(-/-) model confirmed aggravation of mucosal inflammation.

CONCLUSION: Apoptosis of IEC induced by dietary sphingomyelin is mediated via ceramide and cathepsin D activation. This shortens the physiological life cycle of IECs and impairs crucial functions of the intestinal mucosa: barrier, defence and nutrient absorption. The findings provide evidence that dietary sphingomyelin may increase intestinal inflammation.

Statistics

Citations

26 citations in Web of Science®
28 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

74 downloads since deposited on 12 Jan 2011
33 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Gastroenterology and Hepatology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:January 2011
Deposited On:12 Jan 2011 16:19
Last Modified:07 Dec 2017 05:40
Publisher:BMJ Publishing Group
ISSN:0017-5749
Publisher DOI:https://doi.org/10.1136/gut.2009.201988
PubMed ID:21076125

Download

Download PDF  'Sphingomyelin induces cathepsin D-mediated apoptosis in intestinal epithelial cells and increases inflammation in DSS colitis.'.
Preview
Filetype: PDF
Size: 2MB
View at publisher