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The Journal of Immunology, 1998, 161: 2490-2500.
Copyright © 1998 by The American Association of Immunologists

Lipopolysaccharide and Ceramide Use Divergent Signaling Pathways to Induce Cell Death in Murine Macrophages1

Viktor Lakics and Stefanie N. Vogel2

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814

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 Lpsd macrophages were resistant to LPS-induced cell death and less sensitive to C2 ceramide-evoked cytotoxicity, when compared with Lpsn 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.




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