| First Author | Lakics V | Year | 1998 |
| Journal | J Immunol | Volume | 161 |
| Issue | 5 | Pages | 2490-500 |
| PubMed ID | 9725248 | Mgi Jnum | J:112236 |
| Mgi Id | MGI:3655900 | Doi | 10.4049/jimmunol.161.5.2490 |
| Citation | Lakics V, et al. (1998) Lipopolysaccharide and ceramide use divergent signaling pathways to induce cell death in murine macrophages. J Immunol 161(5):2490-500 |
| abstractText | Ceramide is a well-known apoptotic agent that has been implicated in LPS signaling. Therefore, we examined whether LPS-induced macrophage cytotoxicity is mediated by mimicking ceramide. Both LPS and the cell-permeable ceramide analogue, C2 ceramide, induced significant cell death in IFN-gamma-activated, thioglycollate-elicited peritoneal macrophages after 48 and 24 h, respectively. Ceramide-induced cell death was neither accompanied by DNA fragmentation nor phosphatidyl serine externalization, characteristics of apoptosis. In contrast, LPS induced a significant fraction of cells to undergo apoptosis, as demonstrated by DNA fragmentation and quantified by DNA analysis on FACS, yet the majority of the cells died in a necrotic fashion. C3H/HeJ Lps(d) macrophages were resistant to LPS-induced cell death and less sensitive to C2 ceramide-evoked cytotoxicity, when compared with Lps(n) macrophages. C2 ceramide plus IFN-gamma failed to activate release of nitric oxide (NO.), whereas LPS-induced cell death, but not C2-induced cytotoxicity, was blocked by an inhibitor of inducible NO. synthase (iNOS), NG-monomethyl-L-arginine. Macrophages from IFN regulatory factor-1 (-/-) mice shown previously to respond marginally to LPS plus IFN-gamma to express iNOS mRNA and NO., were refractory to LPS plus IFN-gamma-induced cytotoxicity and apoptosis. These data suggest that although LPS may mimic certain ceramide effects, signal transduction events that lead to cytotoxicity, as well as the downstream mediators, diverge. |
