title: Caspase-11 mediates ischemia-induced astrocyte death: involvement of endoplasmic reticulum stress and C/EBP homologous protein.
abstract: Astrocytes are essential cells for maintaining brain integrity. We have recently shown that the transcription factor C/EBP homologous protein (CHOP), associated with endoplasmic reticulum (ER) stress, plays a key role in the astrocyte death induced by ischemia. Meanwhile, mediators of apoptosis downstream of CHOP in the ER stress-dependent pathway remain to be elucidated. Our aim in this work was to determine whether caspase-11, able to activate apoptotic and proinflammatory pathways, is implicated in ER stress-dependent astrocyte death in ischemic conditions. According to our results, caspase-11 is up-regulated in primary astrocyte cultures following either oxygen and glucose deprivation (OGD) or treatment with the ER-stress inducers thapsigargin and tunicamycin. Moreover, these same stimuli increased caspase-11 mRNA levels and luciferase activity driven by a caspase-11 promoter, indicating that caspase-11 is regulated at the transcriptional level. Our data also illustrate the involvement of ER stress-associated CHOP in caspase-11 regulation, insofar as CHOP overexpression by means of an adenoviral vector caused a significant raise in caspase-11. In turn, caspase-11 suppression with siRNA rescued astrocytes from OGD- and ER stress-induced death, supporting the idea that caspase-11 is responsible for the deleterious effects of ischemia on astrocytes. Finally, inhibition of caspase-1 and caspase-3 significantly reduced astrocyte death, which indicates that these proteases act as death effectors of caspase-11. In conclusion, our work contributes to clarifying the pathways leading to astrocyte death in response to ischemia by defining caspase-11 as a key mediator of the ER stress response acting downstream of CHOP.
authors.affiliation: Departamento de Ciencias Médicas and Centro Regional de Investigaciones Biomédicas, Facultad de Medicina, Universidad de Castilla-La Mancha, Albacete, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Fradejas
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Pastor
authors.forename: Miguel
authors.initials: M
authors.lastname: Burgos
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.forename: Pedro
authors.initials: P
authors.lastname: Tranque
authors.forename: Soledad
authors.initials: S
authors.lastname: Calvo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D005822:Genetic Vectors / Q000494:pharmacology; D034622:RNA Interference / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology; D019284:Thapsigargin / Q000633:toxicity; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D014415:Tunicamycin / Q000633:toxicity
chemical_list: D061945:Caspase Inhibitors; D012333:RNA, Messenger; D014415:Tunicamycin; D051742:Transcription Factor CHOP; D019284:Thapsigargin; C491071:Casp4 protein, rat; D020169:Caspases