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The Journal of Neuroscience, May 1, 2002, 22(9):3504-3511
Upregulation of the Fas Receptor Death-Inducing Signaling Complex after Traumatic Brain Injury in Mice and Humans
Jianhua Qiu1, *, Michael J. Whalen1, *, Pedro Lowenstein2, Gary Fiskum3, Brenda Fahy3, Ribal Darwish3, Bizhan Aarabi4, Junying Yuan5, and Michael A. Moskowitz1 1 Neuroscience Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, 2 Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, and Department of Medicine, University of California at Los Angeles, Los Angeles, California 90048, Departments of 3 Anesthesiology and 4 Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, and 5 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115
Recent studies have implicated Fas in the pathogenesis of inflammatory, ischemic, and traumatic brain injury (TBI); however, a direct link between Fas activation and caspase-mediated cell death has not been established in injured brain. We detected Fas-Fas ligand binding and assembly of death-inducing signaling complexes (DISCs) [Fas, Fas-associated protein with death domain, and procaspase-8 or procaspase-10; receptor interacting protein (RIP)-RIP-associated interleukin-1
converting enzyme and CED-3 homolog-1/Ced 3 homologous protein with a death domain-procaspase-2] by immunoprecipitation and immunoblotting within mouse parietal cortex after controlled cortical impact. At the time of DISC assembly, procaspase-8 was cleaved and the cleavage product appeared at 48 hr in terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive neurons. Cleavage of caspase-8 was accompanied by caspase-3 processing detected at 48 hr by immunohistochemistry, and by caspase-specific cleavage of poly(ADP-ribose) polymerase at 12 hr. Fas pathways were also stimulated by TBI in human brain, because Fas expression plus Fas-procaspase-8 interaction were robust in contused cortical tissue samples surgically removed between 2 and 30 hr after injury. To address whether Fas functions as a death receptor in brain cells, cultured embryonic day 17 cortical neurons were transfected with an adenoviral vector containing the gene encoding Fas ligand. After 48 hr in culture, Fas ligand expression and Fas-procaspase-8 DISC assembly increased, and by 72 hr, cell death was pronounced. Cell death was decreased by ~50% after pan-caspase inhibition (Z-Val-ALa-Asp(Ome)-fluoromethylketone). These data suggest that Fas-associated DISCs assemble in neurons overexpressing Fas ligand as well as within mouse and human contused brain after TBI. Therefore, Fas may function as a death receptor after brain injury.
Key words: traumatic brain injury; Fas; death-inducing signaling complex; caspases; human; adenoviral vectors
* J.Q. and M.J.W. contributed equally to this work.
Copyright © 2002 Society for Neuroscience 0270-6474/02/2293504-08$05.00/0
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