Central nervous system-initiated inflammation and neurotrophism in trauma: IL-1 beta is required for the production of ciliary neurotrophic factor.
Injury to the CNS results in the production and accumulation of inflammatory cytokines within this tissue. The origin and role of inflammation within the CNS remains controversial. In this paper we demonstrate that an acute trauma to the mouse brain results in the rapid elevation of IL-1beta. This increase is detectable by 15 min after injury and significantly precedes the influx of leukocytes that occurs hours after. To confirm that IL-1beta up-regulation is initiated by cells within the CNS, in situ hybridization for cytokine transcript was combined with cell type immunohistochemistry. The results reveal parenchymal microglia to be the sole source of IL-1beta at 3 h postinjury. A role for CNS-initiated inflammation was addressed by examining the expression of the neurotrophic factor, ciliary neurotrophic factor (CNTF). Analysis of their temporal relationship suggests the up-regulation of CNTF by IL-1beta, which was confirmed through three lines of evidence. First, the application of IL-1 receptor antagonist into the lesion site attenuated the up-regulation of CNTF. Second, the examination of corticectomized animals genetically deficient for IL-1beta found no CNTF up-regulation. Third, the lack of CNTF elevation in IL-1beta null mice was rescued through exogenous application of IL-1beta into the lesion site. These findings provide the first evidence of the requirement for IL-1beta in the production of CNTF following CNS trauma, and suggest that inflammation can have a beneficial impact on the regenerative capacity of the CNS.
Departments of Clinical Neurosciences and Oncology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
L M
LM
Herx
S
S
Rivest
V W
VW
Yong
D000818:Animals; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D001930:Brain Injuries / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020934:Ciliary Neurotrophic Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005625:Frontal Lobe / Q000473:pathology; D015552:Injections, Intralesional; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D012795:Sialoglycoproteins / Q000008:administration & dosage; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D020934:Ciliary Neurotrophic Factor; D016207:Cytokines; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins