title: Activation of caspase-1 dependent interleukins in developmental brain trauma.
abstract: Focal mechanical cortical trauma triggers diffuse apoptotic neurodegeneration in the developing rat brain which is associated with invasion of brain tissue with inflammatory mediators. We hypothesized that caspase-1 and the two caspase-1-processed cytokines, interleukin (IL)-1beta and IL-18, are involved in trauma-induced neuronal cell death in the developing brain. 7-day-old Wistar rats or C57/BL6 mice were subjected to head trauma using a weight drop device. Animals were sacrificed at defined time points following trauma and brains were processed for histology and molecular analyses. Neuronal cell death in the immature brain peaked at 12-24 h and was accompanied by a marked increase of mRNA and protein levels for caspase-1, IL-1beta and IL-18 within 2 to 12 h following the injury. Caspase-1 levels were elevated for 72 h, whereas IL-1beta decreased earlier at 48 h. IL-18 remained high over a period of 3 days and decreased to normal levels by day 7 after the injury. Intraperitoneal injection of recombinant human IL-18-binding protein (IL-18BP), a specific inhibitor of IL-18, attenuated traumatic brain injury. Mice deficient in IL-18 (IL-18-/-) were protected against trauma-induced brain damage. These findings indicate that IL-18 is involved in trauma-induced neuronal cell death in the immature rodent brain and might serve as a potential therapeutic target.
authors.affiliation: Department of Pediatric Neurology, Children's Hospital, Medical Faculty Carl Gustav Carus, Technical University Dresden, 01307 Dresden, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Sifringer
authors.forename: Vanya
authors.initials: V
authors.lastname: Stefovska
authors.forename: Stefanie
authors.initials: S
authors.lastname: Endesfelder
authors.forename: Philip F
authors.initials: PF
authors.lastname: Stahel
authors.forename: Kerstin
authors.initials: K
authors.lastname: Genz
authors.forename: Mark
authors.initials: M
authors.lastname: Dzietko
authors.forename: Chrysanthy
authors.initials: C
authors.lastname: Ikonomidou
authors.forename: Ursula
authors.initials: U
authors.lastname: Felderhoff-Mueser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D001930:Brain Injuries / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009410:Nerve Degeneration / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D020382:Interleukin-18; D053583:Interleukin-1beta; D012333:RNA, Messenger; D020170:Caspase 1