E: vidence suggests that tumor necrosis factor a (TNFa) and interleukin-18 (IL-18) employ the sphingomyelin pathway to effect signal transduction by their receptors. This pathway is initiated by hydrolysis of plasma membrane sphingomyelin to ceramide by the action of a sphingomyelinase. Ceramide serves as asecond messenger, stimulating a serine/threonine ceramide-activated protein kinase to transduce the cytokine signal, in part through mitogenactivated protein (MAP) kinase and transcription factors such as NF-KB (Figure 1). The extent to which this signaling system is used in inflammation, immune responses, and apoptosis is not known, but accumulating evidence suggests that it is a commonly employed pathway that could be exploited therapeutically. The Sphingomyelin Metabolic Pathway Sphingomyelin is preferentially concentrated in the outer leaflet of the plasma membrane of most mammalian cells; it is comprised of a long chain sphingoid base backbone (predominantly sphingosine), a fatty acid, and a phosphocholine head group (Figure 2). The fatty acid in amide linkage at the second position of the sphingoid base constitutes ceramide. Hydrolysis of the phosphodiester bond by a sphingomyelinase to yield ceramide and phosphocholine is the only clearly defined mechanism for sphingomyelin degradation in mammalian cells (Kolesnick, 1991). Sphingomyelin was considered only a structural element of the plasma membrane. However, 1, 2-diacylglycerol (DG), a physiologic activator of protein kinase C, stimulated rapid sphingomyelin degradation toceramide in GH3 rat pituitary cells (Kolesnick, 1991). Little of the generated ceramide was deacylated to sphingoid bases, potential inhibitors of protein kinase C (Hannun and Bell, 1989), prompting a search for additional derivatives of ceramide. Several investigations established the existence of a specific metabolic pathway from sphingomyelin to ceramide l-phosphate (see Bajjalieh et al., 1989; Kolesnick, 1991). The sphingomyelin metabolic pathway is similar to the phosphoinositide signal transduction pathway. The central lipids in these pathways, ceramide and DG, both serve as substrates for the same bacterial DG kinase, implying they possess structural similarity. Their phosphorylated forms, ceramide l-phosphate and phosphatidic acid, were, therefore, also structurally similar. Further, neutral sphingomyelinase, the enzyme that initiates the sphingomyelin pathway, is a phospholipase C concentrated in the plasma membrane (Kolesnick, 1991) like the enzyme initiating the phosphoinositide pathway. Ceramide also appears to be an ideal candidate second messenger since it readily redistributes across a membrane bilayer (Lipsky and Pagano, 1985). Since DG utilized a specific kinase, protein kinase C, for signaling, it was considered that ceramide might stimulate a kinase. Ceramide does not activate protein kinase C.