DEFECTIVE CERAMIDE RESPONSE IN C3H HEJ (LPS(D)) MACROPHAGES/

Lipid second messengers are gaining recognition as important mediators of extracellular signals. One such lipid, ceramide, generated from me mbrane sphingomyelin following stimulation with TNF-alpha, IL-1 beta, or IFN-gamma, activates ceramide-activated kinase (CAK). A recent stud y demonstrated that LPS activated CAK without generating ceramide, sug gesting that the LPS stimulation of cells mimics the second messenger function of ceramide. To compare ceramide to LPS signaling, we assesse d the ability of LPS-responsive (Lps(n)) and LPS-hyporesponsive (Lps(d )) macrophages to respond directly to ceramide for enhanced expression of LPS-inducible genes. In contrast to macrophages from C3H/OuJ (Lps( n)) mice, C3H/HeJ (Lps(d)) macrophages failed to respond to cell-perme able analogues of ceramide (C-2,C-6,C-16) or sphingomyelinase. These r esults suggest that a common critical molecule, encoded by the Lps gen e, regulates both ceramide and LPS signaling pathways.