title: Caspase-1-processed interleukins in hyperoxia-induced cell death in the developing brain.
abstract: Infants born prematurely may develop neurocognitive deficits without an obvious cause. Oxygen, which is widely used in neonatal medicine, constitutes one possible contributing neurotoxic factor, because it can trigger neuronal apoptosis in the developing brain of rodents. We hypothesized that two caspase-1-processed cytokines, interleukin (IL)-1beta and IL-18, are involved in oxygen-induced neuronal cell death. Six-day-old Wistar rats or C57/BL6 mice were exposed to 80% oxygen for various time periods (2, 6, 12, 24, and 48 hours). Neuronal cell death in the brain, as assessed by Fluoro-Jade B and silver staining, peaked at 12 to 24 hours and was preceded by a marked increase in mRNA and protein levels of caspase 1, IL-1beta, IL-18, and IL-18 receptor alpha (IL-18Ralpha). Intraperitoneal injection of recombinant human IL-18-binding protein, a specific inhibitor of IL-18, attenuated hyperoxic brain injury. Mice deficient in IL-1 receptor-associated kinase 4 (IRAK-4), which is pivotal for both IL-1beta and IL-18 signal transduction, were protected against oxygen-mediated neurotoxicity. These findings causally link IL-1beta and IL-18 to hyperoxia-induced cell death in the immature brain. These cytokines might serve as useful targets for therapeutic approaches aimed at preserving neuronal function in the immature brain, which is exquisitely sensitive to a variety of iatrogenic measures including oxygen.
authors.affiliation: Department of Neonatology, Charité, Campus Virchow Klinikum, Humboldt University Medical Center, Augustenburger Platz 1, D-13353 Berlin, Germany. ursula.felderhoff@charite.de
authors.forename: Ursula
authors.initials: U
authors.lastname: Felderhoff-Mueser
authors.forename: Marco
authors.initials: M
authors.lastname: Sifringer
authors.forename: Oliver
authors.initials: O
authors.lastname: Polley
authors.forename: Mark
authors.initials: M
authors.lastname: Dzietko
authors.forename: Birgit
authors.initials: B
authors.lastname: Leineweber
authors.forename: Lieselotte
authors.initials: L
authors.lastname: Mahler
authors.forename: Michael
authors.initials: M
authors.lastname: Baier
authors.forename: Petra
authors.initials: P
authors.lastname: Bittigau
authors.forename: Michael
authors.initials: M
authors.lastname: Obladen
authors.forename: Chrysanthy
authors.initials: C
authors.lastname: Ikonomidou
authors.forename: Christoph
authors.initials: C
authors.lastname: Bührer
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000473:pathology*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018496:Hyperoxia / Q000473:pathology; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D007375:Interleukin-1 / Q000494:pharmacology*; D053592:Interleukin-1 Receptor-Associated Kinases; D020382:Interleukin-18 / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000633:toxicity; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors
chemical_list: D007375:Interleukin-1; D020382:Interleukin-18; D012333:RNA, Messenger; D017853:Phosphotransferases (Alcohol Group Acceptor); D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse; D020170:Caspase 1; D010100:Oxygen