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Originally published In Press as doi:10.1074/jbc.M106653200 on November 12, 2001

J. Biol. Chem., Vol. 277, Issue 6, 4285-4293, February 8, 2002
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Ceramide Generation in Situ Alters Leukocyte Cytoskeletal Organization and beta 2-Integrin Function and Causes Complete Degranulation*

Michael J. FeldhausDagger §, Andrew S. Weyrich||, Guy A. Zimmerman||, and Thomas M. McIntyreDagger ||**

From the Departments of  Medicine and Dagger  Pathology and the || Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah 84112

Ceramide levels increase in activated polymorphonuclear neutrophils, and here we show that endogenous ceramide induced degranulation and superoxide generation and increased surface beta 2-integrin expression. Ceramide accumulation reveals a bifurcation in integrin function, as it abolished agonist-induced adhesion to planar surfaces, yet had little effect on homotypic aggregation. We increased cellular ceramide content by treating polymorphonuclear neutrophils with sphingomyelinase C and controlled for loss of sphingomyelin by pretreatment with sphingomyelinase D to generate ceramide phosphate, which is not a substrate for sphingomyelinase C. Pretreatment with the latter enzyme blocked all the effects of sphingomyelinase C. Ceramide generation caused a Ca2+ flux and complete degranulation of both primary and secondary granules and increased surface beta 2-integrin expression. These integrins were in a nonfunctional state, and subsequent activation with platelet-activating factor or formyl-methionyl-leucyl-phenylalanine induced beta 2-integrin-dependent homotypic aggregation. However, these cells were completely unable to adhere to surfaces via beta 2-integrins. This was not due to a defect in the integrins themselves because the active conformation could be achieved by cation switching. Rather, ceramide affected cytoskeletal organization and inside-out signaling, leading to affinity maturation. Cytochalasin D induced the same disparity between aggregation and surface adhesion. We conclude that ceramide affects F-actin rearrangement, leading to massive degranulation, and reveals differences in beta 2-integrin-mediated adhesive events.

* This work was supported by National Institutes of Health Grant HL50153 P50 and by a grant from the Nora Eccles Treadwell Foundation. The flow facility was supported by NCI Grant Cancer Center Support Grant CA42014 from the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Present address: Pacific Northwest National Labs., Richland, WA 99652.

** To whom correspondence should be addressed: 4130 EIHG, University of Utah, Salt Lake City, UT 84112-5330. Tel.: 801-585-0716; Fax: 801-585-0701; E-mail: tom.mcintyre@hmbg.utah.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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