The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/5/1581/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 10, May 17, 1999 1581-1589

Articles

A Role for Neutral Sphingomyelinase-mediated Ceramide Production in T Cell Receptor–induced Apoptosis and Mitogen-activated Protein Kinase–mediated Signal Transduction

Laura Tonnetti*, Maria-Concetta Verí{ddagger}, Ezio Bonvini{ddagger}, and Luciano D'Adamio*

From the * T-Cell Apoptosis Unit, Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892; and the {ddagger} Laboratory of Immunobiology, Division of Monoclonal Antibodies, Center for Biologics Evaluation and Research, Bethesda, Maryland 20892

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-induced interleukin (IL)-2 production and programmed cell death. Addition of either exogenous ceramide or bacterial sphingomyelinase reconstituted both responses. Moreover, specific inactivation of neutral sphingomyelinase by antisense RNA inhibited IL-2 production and mitogen-activated protein kinase activation after TCR triggering. These results suggest that ceramide production by activation of neutral sphingomyelinase is an essential component of the TCR signaling machinery.

Key Words: neutral sphingomyelinase • ceramide • T cell receptor • signaling • activation • apoptosis

Address correspondence to Luciano D'Adamio, T-Cell Apoptosis Unit, Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. Phone: 301-496-3842; Fax: 301-402-3184; E-mail: ldadamio{at}atlas.niaid.nih.gov

Abbreviations used: aSMase, bSMase, and nSMase, acidic, bacterial, and neutral SMase; CM, ceramide; CoA, coenzyme A; CsA, cyclosporin A; EGFP, enhanced green fluorescent protein; Erk, extracellular signal regulatory kinase; FB1, fumonisin B1; MAP, mitogen-activated protein; PCD, programmed cell death; PKC, protein kinase C; PLC, phospholipase C; SM, sphingomyelin; SMase, sphingomyelinase.


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