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The Journal of Neuroscience, March 22, 2006, 26(12):3299-3308; doi:10.1523/JNEUROSCI.5572-05.2006

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Cellular/Molecular
Human Astrocytes Are Resistant to Fas Ligand and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis

Jin H. Song,¹ Anita Bellail,¹ Margaret C. L. Tse,¹ V. Wee Yong,² and Chunhai Hao¹

¹Department of Pathology and Laboratory Medicine, Center of Neurodegenerative Disease and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, and ²Department of Oncology and Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada T2N 4N1

Correspondence should be addressed to Dr. Chunhai Hao, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 1365-C Clifton Road NE, Atlanta, GA 30322. Email: chao{at}emory.edu

Human astrocytes express Fas yet are resistant to Fas-induced apoptosis. Here, we report that calcium/calmodulin-dependent protein kinase II (CaMKII) is constitutively activated in human astrocytes and protects the cells from apoptotic stimulation by Fas agonist. Once stimulated, Fas recruits Fas-associated death domain and caspase-8 for the assembly of the death-inducing signaling complex (DISC); however, caspase-8 cleavage is inhibited in the DISC. Inhibition of CaMKII kinase activity inhibits the expression of phosphoprotein enriched astrocytes-15 kDa/phosphoprotein enriched in diabetes (PEA-15/PED) and cellular Fas-associated death domain-like interleukin-1-converting enzyme-inhibitory protein (c-FLIP), thus releasing their inhibition of caspase-8 cleavage. Inhibition of PEA-15/PED or c-FLIP by small interfering RNA sensitizes human astrocytes to Fas-induced apoptosis. In contrast, inhibition of CaMKII, PEA-15, or c-FLIP does not affect the sensitivity of human astrocytes to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL death receptors (DR4, DR5) are weakly expressed at mRNA, protein, and cell surface levels and thus fail to mediate the assembly of the DISC in human astrocytes. Overexpression of DR5 restores TRAIL signaling pathways and sensitizes the human astrocytes to TRAIL-induced apoptosis if CaMKII kinase activity or expression of PEA-15 and c-FLIP is inhibited; the results suggest that CaMKII-mediated pathways prevent TRAIL-induced apoptosis in human astrocytes under conditions in which TRAIL death receptors are upregulated. This study has therefore identified the molecular mechanisms that protect normal human astrocytes from apoptosis induced by Fas ligand and TRAIL.

Key words: apoptosis; astrocytes; CaMKII; c-FLIP; Fas; TRAIL

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Received Aug. 22, 2005; revised Jan. 27, 2006; accepted Feb. 9, 2006.

Correspondence should be addressed to Dr. Chunhai Hao, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 1365-C Clifton Road NE, Atlanta, GA 30322. Email: chao{at}emory.edu

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