Caspase-8 expression and proteolysis in human brain after severe head injury.
Programmed cell death involves a complex and interrelated cascade of cysteine proteases termed caspases that are synthesized as inactive zymogens, which are proteolytically processed to active enzymes. Caspase-8 is an initiator caspase that becomes activated when Fas death receptor-Fas ligand (FasL) coupling on the cell surface leads to coalescence of a "death complex" perpetuating the programmed cell death cascade. In this study, brain tissue samples removed from adult patients during the surgical management of severe intracranial hypertension after traumatic brain injury (TBI; n=17) were compared with postmortem control brain tissue samples (n=6). Caspase-8 mRNA was measured by semiquantitative reverse transcription and polymerase chain reaction, and caspase-8 protein was examined by Western blot and immunocytochemistry. Fas and FasL were also examined using Western blot. Caspase-8 mRNA and protein were increased in TBI patients vs. controls, and caspase-8 protein was predominately expressed in neurons. Proteolysis of caspase-8 to 20-kDa fragments was seen only in TBI patients. Fas was also increased after TBI vs. control and was associated with relative levels of caspase-8, supporting formation of a death complex. These data identify additional steps in the programmed cell death cascade involving Fas death receptors and caspase-8 after TBI in humans.
Zhang
Xiaopeng
X
Department of Critical Care Medicine, The Safar Center for Resuscitation Research and the Brain Trauma Research Center, University of Pittsburgh, PA 15260, USA.
Graham
Steven H
SH
Kochanek
Patrick M
PM
Marion
Donald W
DW
Nathaniel
Paula D
PD
Watkins
Simon C
SC
Clark
Robert S B
RS
D000367:Age Factors; D017209:Apoptosis; D001921:Brain / Q000201:enzymology*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D053222:Fas Ligand Protein; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D019586:Intracranial Hypertension / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000201:enzymology; D012333:RNA, Messenger / Q000096:biosynthesis; D019014:fas Receptor / Q000096:biosynthesis
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases