Universität zu Köln

El-Hindi, Khadija, Brachtendorf, Sebastian, Hartel, Jennifer Christina, Oertel, Stephanie, Birod, Kerstin, Trautmann, Sandra, Thomas, Dominique ORCID: 0000-0002-4153-3669, Ulshoefer, Thomas, Weigert, Andreas ORCID: 0000-0002-7529-1952, Utermoehlen, Olaf, Kroenke, Martin and Groesch, Sabine (2020). Ceramide Synthase 5 Deficiency Aggravates Dextran Sodium Sulfate-Induced Colitis and Colon Carcinogenesis and Impairs T-Cell Activation. Cancers, 12 (7). BASEL: MDPI. ISSN 2072-6694

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Abstract

Ceramide synthase 5 is one of six enzymes that catalyze the production of ceramides from sphingosine or sphinganine. Ceramides are important components of cell membranes and act as signaling molecules. Previously it has been shown that ceramide synthase 6 and 2 influence colitis in several animal models with sometimes opposite effects. Here, we investigated the disease course of dextran sodium sulfate-induced acute colitis and azoxymethane/dextran sodium sulfate-induced colitis-associated colon cancer in mice with global ceramide synthase 5 knockout (CerS5-ko) or with ceramide synthase 5 knockout restricted to the colon epithelium (CerS5fl/fl VilCre). We monitored disease development and analyzed colon barrier function as well as the immune cell status in these mice. CerS5-ko mice but not CerS5fl/fl-VilCre mice were more susceptible to acute and chronic inflammation. However, the cell barrier function of colon epithelial cells was not disturbed by downregulation of ceramide synthase 5. Instead, untreated CerS5-ko mice displayed reduced numbers of CD3(+)immune cells in the spleen, colon, and blood, especially of intraepithelial CD8(+)T-cells, which was not obvious in CerS5fl/fl Vil Cre mice. Reduced T-cell number in colon tissue of CerS5-ko mice was accompanied by a reduced expression of IL-1 beta, IFN gamma, and IL-4. In vitro investigations revealed that knockdown of ceramide synthase 5 in T-cells impaired T-cell activation. In summary, we show that CerS5-ko mice were more susceptible to dextran sodium sulfate-induced colitis and azoxymethane/dextran sodium sulfate-induced colitis-associated colon cancer. A reduced number of T-cells in the colon epithelium that was already the case in untreated CerS5-ko mice might have contributed to this effect.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code El-Hindi, Khadija UNSPECIFIED UNSPECIFIED UNSPECIFIED Brachtendorf, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartel, Jennifer Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Oertel, Stephanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Birod, Kerstin UNSPECIFIED UNSPECIFIED UNSPECIFIED Trautmann, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Thomas, Dominique UNSPECIFIED orcid.org/0000-0002-4153-3669 UNSPECIFIED Ulshoefer, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Weigert, Andreas UNSPECIFIED orcid.org/0000-0002-7529-1952 UNSPECIFIED Utermoehlen, Olaf UNSPECIFIED UNSPECIFIED UNSPECIFIED Kroenke, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Groesch, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-327500
DOI:	10.3390/cancers12071753
Journal or Publication Title:	Cancers
Volume:	12
Number:	7
Date:	2020
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2072-6694
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; LYMPHOCYTES; TCR; SPHINGOSINE-1-PHOSPHATE; METABOLISM; CANCER Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/32750