T-Cell-Specific CerS4 Depletion Prolonged Inflammation and Enhanced Tumor Burden in the AOM/DSS-Induced CAC Model

• Published in: International journal of molecular sciences 2022-02, Vol.23 (3), p.1866
• Main Authors: El-Hindi, Khadija, Brachtendorf, Sebastian, Hartel, Jennifer Christina, Oertel, Stephanie, Birod, Kerstin, Merz, Nadine, Trautmann, Sandra, Thomas, Dominique, Weigert, Andreas, Schäufele, Tim J, Scholich, Klaus, Schiffmann, Susanne, Ulshöfer, Thomas, Utermöhlen, Olaf, Grösch, Sabine
• Format: Article
• Language: English
• Subjects: Animals; Azoxymethane; Azoxymethane - adverse effects; CD8 antigen; Cell proliferation; ceramide synthase; Colitis; Colitis-Associated Neoplasms - chemically induced; Colitis-Associated Neoplasms - genetics; Colitis-Associated Neoplasms - immunology; Colitis-Associated Neoplasms - pathology; Colon; Colonic Neoplasms - chemically induced; Colonic Neoplasms - genetics; Colonic Neoplasms - immunology; Colonic Neoplasms - pathology; Colorectal cancer; Cytokines; Depletion; Dextran; Dextran Sulfate - adverse effects; Dextrans; Disease Models, Animal; Epithelial cells; Epithelium; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Jurkat; Jurkat Cells; LASS; Lck protein; Lymphocytes T; Mice; Mice, Knockout; NF-kappa B - metabolism; NF-κB protein; Organ Specificity; Receptors, Antigen, T-Cell - metabolism; Rodents; Signal Transduction; Small intestine; Sphingolipids; Sphingosine N-Acyltransferase - genetics; T cell receptors; T-cell; T-Lymphocytes - metabolism; tumor; Tumor Burden; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23031866

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.