82 Oxygen Induces Neurodegeneration Triggered by Production Of Caspase-1 Processed Interleukins IL-1 and IL-18

Abstract

Backgound/Aims: A proportion of infants born preterm suffer from neurodevelopmental deficits with undefined pathogenesis. Oxygen has been shown to cause widespread neurodegeneration in the immature rat and mouse brain. We hypothesized that the two caspase-1-processed cytokines, interleukin(IL)-1â and IL-18, are involved in oxygen-induced neuronal cell death. Methods: Six day-old Wistar rats or C57/BL6 mice were exposed to 80% oxygen for various time periods (2, 6, 12, 24, 48 hours). Brain tissue was processed for either histology or RT-PCR and Western Blotting. Results: Neuronal cell death, as assessed by fluoro jade or silver staining, peaked at 12 - 24 h, preceded by a marked mRNA and protein upregulation of caspase-1, IL-1â, IL-18 and IL-18 receptor-alpha (Il-18R alpha). When rats were intraperitoneally injected with recombinant human IL-18-binding protein (IL-18BP), a specific inhibitor of IL-18, brain injury in response to increased oxygen was attenuated. Mice deficient in interleukin-1 receptor (IL-1R)-associated kinase-4 (IRAK-4), which is pivotal for both IL-1â and IL-18 intracelluar signal transduction, were largely protected against oxygen-mediated neurotoxicity. Conclusion: These findings suggest involvement of IL-1â and IL-18 in the pathogenesis leading to hyperoxia-induced neuronal cell death in the immature brain. IL-1â and IL-18 could be useful targets for therapeutic approaches aimed at preserving neuronal function following oxygen-induced injury to the developing brain. (supported by BMBF grant Z 0101)