| The central nervous system (CNS) response to injury is characterized by the rapid activation of astrocytes in a process known as reactive astrogliosis. Astrogliosis has traditionally been thought to impede regeneration, but evidence involving the astroglial production of neurotrophic factors suggests that it is an intrinsic attempt by the CNS to promote recovery, albeit, a failed one. Identification of the molecular mediators involved in regulating astrogliosis is necessary for establishing suitable conditions for regeneration and remyelination. Injury to the CNS also results in the production of inflammatory cytokines, such as interleukin-1 (IL-1)beta, and previous work from our lab has implied a role for such cytokines in the mediation of astrogliosis. The role of inflammation within the CNS, however, remains controversial. This thesis tests the hypothesis that IL-1beta is an important orchestrator of the CNS response to trauma, involved in the regulation of astrogliosis and neurotrophic factor production.; Our results demonstrate that an acute brain trauma results in the rapid elevation of IL-1beta within 15 minutes following injury, that was 100% colocalized to parenchymal microglia at 3 hours post-injury. The increase in IL-1beta preceded the elevation of the neurotrophic factor, ciliary neurotrophic factor (CNTF). A role for IL-1beta in regulating CNTF was confirmed through three lines of evidence. First, application of IL-1 receptor antagonist into the lesion site attenuated CNTF upregulation. Second, corticectomized animals genetically deficient for IL-1beta failed to upregulate CNTF. Third, the lack of CNTF elevation in IL-1beta -/- mice was rescued through exogenous application of IL-1beta into the lesion. The elevation of glial fibrillary acidic protein (GFAP) transcripts, a reliable indicator of astrogliosis, also followed the elevation of IL-1beta mRNA after trauma, and the injury-induced upregulation of GFAP mRNA did not occur in IL-1beta null mice. This correlated to an absence in GFAP-immunoreactivity that recovered by 5 to 7 days post-injury. Functionally, mice lacking IL-1beta exhibited a significant impairment in reformation of the blood-brain barrier (BBB) following corticectomy.; These findings provide the first in vivo evidence for IL-1beta in the regulation of CNTF production following CNS trauma, suggesting that inflammation can have a beneficial impact on the regenerative capacity of the CNS. And furthermore, that the rapid upregulation of IL-1beta following CNS trauma plays a role in initiating astrogliosis and restoring the integrity of the BBB. |
