TY  - JOUR
A1  - El-Hindi, Khadija
A1  - Brachtendorf, Sebastian
A1  - Hartel, Jennifer
A1  - Oertel, Stephanie
A1  - Birod, Kerstin
A1  - Merz, Nadine
A1  - Trautmann, Sandra
A1  - Thomas, Dominique
A1  - Weigert, Andreas
A1  - Schäufele, Tim J.
A1  - Scholich, Klaus
A1  - Schiffmann, Susanne
A1  - Ulshöfer, Thomas
A1  - Utermöhlen, Olaf
A1  - Grösch, Sabine
T1  - T-Cell-Specific CerS4 Depletion Prolonged Inflammation and Enhanced Tumor Burden in the AOM/DSS-Induced CAC Model
T2  - International journal of molecular sciences
N2  - To better understand the role of sphingolipids in the multifactorial process of inflammatory bowel disease (IBD), we elucidated the role of CerS4 in colitis and colitis-associated cancer (CAC). For this, we utilized the azoxymethane/dextran sodium sulphate (AOM/DSS)-induced colitis model in global CerS4 knockout (CerS4 KO), intestinal epithelial (CerS4 Vil/Cre), or T-cell restricted knockout (CerS4 LCK/Cre) mice. CerS4 KO mice were highly sensitive to the toxic effect of AOM/DSS, leading to a high mortality rate. CerS4 Vil/Cre mice had smaller tumors than WT mice. In contrast, CerS4 LCK/Cre mice frequently suffered from pancolitis and developed more colon tumors. In vitro, CerS4-depleted CD8+ T-cells isolated from the thymi of CerS4 LCK/Cre mice showed impaired proliferation and prolonged cytokine production after stimulation in comparison with T-cells from WT mice. Depletion of CerS4 in human Jurkat T-cells led to a constitutively activated T-cell receptor and NF-κB signaling pathway. In conclusion, the deficiency of CerS4 in T-cells led to an enduring active status of these cells and prevents the resolution of inflammation, leading to a higher tumor burden in the CAC mouse model. In contrast, CerS4 deficiency in epithelial cells resulted in smaller colon tumors and seemed to be beneficial. The higher tumor incidence in CerS4 LCK/Cre mice and the toxic effect of AOM/DSS in CerS4 KO mice exhibited the importance of CerS4 in other tissues and revealed the complexity of general targeting CerS4.
KW  - ceramide synthase
KW  - LASS
KW  - colon
KW  - tumor
KW  - T-cell
KW  - Jurkat
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/81023
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-810239
SN  - 1422-0067
N1  - This research was funded by Deutsche Forschungs Gemeinschaft (DFG), SFB1039, GR 2011/7-1.
VL  - 23
IS  - 3, art.  1866
SP  - 1
EP  - 24
PB  - Molecular Diversity Preservation International
CY  - Basel
ER  -