| First Author | Lamour NF | Year | 2011 |
| Journal | J Biol Chem | Volume | 286 |
| Issue | 50 | Pages | 42808-17 |
| PubMed ID | 22009748 | Mgi Jnum | J:178716 |
| Mgi Id | MGI:5299977 | Doi | 10.1074/jbc.M111.310169 |
| Citation | Lamour NF, et al. (2011) Ceramide Kinase Regulates the Production of Tumor Necrosis Factor alpha (TNFalpha) via Inhibition of TNFalpha-converting Enzyme. J Biol Chem 286(50):42808-17 |
| abstractText | Tumor necrosis factor alpha (TNFalpha) is a well known cytokine involved in systemic and acute inflammation. In this study, we demonstrate that ceramide 1-phosphate (C1P) produced by ceramide kinase (CERK) is a negative regulator of LPS-induced TNFalpha secretion. Specifically, bone marrow-derived macrophages isolated from CERK knock-out mice (CERK(-/-)) generated higher levels of TNFalpha than the wild-type mice (CERK(+/+)) in response to LPS. An increase in basal TNFalpha secretion was also observed in CERK(-/-) murine embryonic fibroblasts, which was rescued by re-expression of wild-type CERK. This effect was due to increased secretion and not transcription. The secretion of TNFalpha is regulated by TNFalpha-converting enzyme (TACE also known as ADAM17), and importantly, the activity of TACE was higher in cell extracts from CERK(-/-) as compared with wild type. In vitro analysis also demonstrated that C1P is a potent inhibitor of this enzyme, in stark contrast to ceramide and sphingosine 1-phosphate. Furthermore, TACE specifically bound C1P with high affinity. Finally, several putative C1P-binding sites were identified via homology throughout the protein sequence of TACE. These results indicate that C1P produced by CERK has a negative effect on the processing/secretion of TNFalpha via modulation of TACE activity. |
