A role for neutral sphingomyelinase-mediated ceramide production in T cellreceptor-induced apoptosis and mitogen-activated protein kinase-mediated signal transduction

Studying apoptosis induced by T cell receptor (TCR) cross-linking in the T cell hybridoma, 3DO, we found both neutral sphingomyelinase activation and production of ceramide upon receptor engagement. Pharmacological inhibition of ceramide production by the fungal toxin, fumonisin B1, impaired TCR-ind uced interleukin (IL)-2 production and programmed cell death. Addition of e ither exogenous ceramide or bacterial sphingomyelinase reconstituted both r esponses. Moreover, specific inactivation of neutral sphingomyelinase by an tisense RNA inhibited IL-2 production and mitogen-activated protein kinase activation after TCR triggering. These results suggest that ceramide produc tion by activation of neutral sphingomyelinase is an essential component of the TCR signaling machinery.