The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/2/481/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 3, February 3, 1997 481-490

Articles

Cytokine Response Modifier A (CrmA) Inhibits Ceramide Formation in Response to Tumor Necrosis Factor (TNF)-{alpha}: CrmA and Bcl-2 Target Distinct Components in the Apoptotic Pathway

Ghassan S. Dbaibo*, David K. Perry{ddagger}, Chris J. Gamard{ddagger}, Rheanna Platt{ddagger}, Guy G. Poirier, Lina M. Obeid, and Yusuf A. Hannun

From the * Department of Pediatrics, {ddagger} Department of Medicine, and Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710; and the {ddagger}Laboratory of Molecular Endocrinology, Laval University, Sainte-Foy, Quebec, G1V-4G2, Canada

Proteases are now firmly established as major regulators of the "execution" phase of apoptosis. Here, we examine the role of proteases and their relationship to ceramide, a proposed mediator of apoptosis, in the tumor necrosis factor-{alpha} (TNF-{alpha})–induced pathway of cell death. Ceramide induced activation of prICE, the protease that cleaves the death substrate poly(ADP-ribose) polymerase. Bcl-2 inhibited ceramide-induced death, but not ceramide generation. In contrast, Cytokine response modifier A (CrmA), a potent inhibitor of Interleukin-1β converting enzyme and related proteases, inhibited ceramide generation and prevented TNF-{alpha}–induced death. Exogenous ceramide could overcome the CrmA block to cell death, but not the Bcl-2 block. CrmA, however, did not inhibit the activation of nuclear factor (NF)-{kappa}B by TNF-{alpha}, demonstrating that other signaling functions of TNF-{alpha} remain intact and that ceramide does not play a role in the activation of NF-{kappa}B. These studies support a distinct role for proteases in the signaling/activation phase of apoptosis acting upstream of ceramide formation.

Address correspondence to Yusuf A. Hannun, Duke University Medical Center, Box 3355, Durham, NC 27710.

This work was supported by a National Institute of Child Health and Human Development grant 5P30HD28828-03 to G. Dbaibo, National Institutes of Health grant GM-43825 to Y. Hannun, and Department of the Army Medical Division grant 17-94-J4301 to Y. Hannun.

1Abbreviations used in this paper: CrmA, cytokine response modifier A; FBS, fetal bovine serum; ICE, IL-1β converting enzyme; NF, nuclear factor; PARP, poly(ADP-ribose) polymerase.


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