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The Critical Role of Protein Kinase C- in Fas/Fas Ligand-Mediated Apoptosis¹

Department of Microbiology and Immunology, School of Medicine, University of Illinois, Chicago, IL 60612

A functional immune system not only requires rapid expansion of antigenic specific T cells, but also requires efficient deletion of clonally expanded T cells to avoid accumulation of T cells. Fas/Fas ligand (FasL)-mediated apoptosis plays a critical role in the deletion of activated peripheral T cells, which is clearly demonstrated by superantigen-induced expansion and subsequent deletion of T cells. In this study, we show that in the absence of protein kinase C- (PKC-), superantigen (staphylococcal enterotoxin B)-induced deletion of V8⁺ CD4⁺ T cells was defective in PKC-^–/– mice. In response to staphylococcal enterotoxin B challenge, up-regulation of FasL, but not Fas, was significantly reduced in PKC-^–/– mice. PKC- is thus required for maximum up-regulation of FasL in vivo. We further show that stimulation of FasL expression depends on PKC--mediated activation of NF-AT pathway. In addition, PKC-^–/– T cells displayed resistance to Fas-mediated apoptosis as well as activation-induced cell death (AICD). In the absence of PKC-, Fas-induced activation of apoptotic molecules such as caspase-8, caspase-3, and Bid was not efficient. However, AICD as well as Fas-mediated apoptosis of PKC-^–/– T cells were restored in the presence of high concentration of IL-2, a critical factor required for potentiating T cells for AICD. PKC- is thus required for promoting FasL expression and for potentiating Fas-mediated apoptosis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from American Cancer Society of Illinois Division, Schweppe Foundation, University of Illinois Cancer Center and University of Illinois Institutional Review Board, and National Institutes of Health Grant R01-AI053147-01.

² Address correspondence and reprint requests to Dr. Zuoming Sun, Department of Microbiology and Immunology, College of Medicine, University of Illinois, 835 South Wolcott (M/C790), Chicago, IL 60612. E-mail address: zuoming{at}uic.edu

³ Abbreviations used in this paper: AICD, activation-induced cell death; FasL, Fas ligand; DAG, diacylglycerol; EAE, experimental allergic encephalomyelitis; IP₃, inositol triphosphate; PKC, protein kinase C; SEB, staphylococcal enterotoxin B; siRNA, small interfering RNA; WT, wild type.

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