Astrogliosis in the neonatal and adult murine brain post-trauma: elevation of inflammatory cytokines and the lack of requirement for endogenous interferon-gamma.
The relevance of astrogliosis remains controversial, especially with respect to the beneficial or detrimental influence of reactive astrocytes on CNS recovery. This dichotomy can be resolved if the mediators of astrogliosis are identified. We have measured the levels of transcripts encoding inflammatory cytokines in injury systems in which the presence or absence of astrogliosis could be produced selectively. A stab injury to the adult mouse brain using a piece of nitrocellulose (NC) membrane elicited a prompt and marked increase in levels of transcripts for interleukin (IL)-1alpha, IL-1beta, and tumor necrosis factor (TNF)-alpha, which are considered to be microglia/macrophage cytokines. The elevations preceded, or occurred concomitantly with, the rise in glial fibrillary acidic protein mRNA, an early manifestation of astrogliosis. In neonatal mice, IL-1 and TNF-alpha mRNA were elevated to a greater extent by an NC-implant injury, which produced astrogliosis, than after an NC-stab, with minimal astrogliosis. We determined whether endogenous interferon (IFN)-gamma could be responsible for the observed increases in IL-1 and TNF-alpha, because IFN-gamma is a potent microglia/macrophage activator, and because its exogenous administration to rodents enhanced astrogliosis after adult or neonatal insults. A lack of requirement for endogenous IFN-gamma was demonstrated by three lines of evidence. First, no increase in IFN-gamma transcripts could be found at injury. Second, the administration of a neutralizing antibody to IFN-gamma did not attenuate astrogliosis. Third, in IFN-gamma knockout adult mice, astrogliosis and increases in levels of IL-1alpha and TNF-alpha were induced rapidly by injury. The marked elevation of inflammatory cytokines is discussed in the context of astrogliosis and general CNS recovery.
Rostworowski
M
M
Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
Balasingam
V
V
Chabot
S
S
Owens
T
T
Yong
V W
VW
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D001930:Brain Injuries / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D005911:Gliosis / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014947:Wounds and Injuries / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014951:Wounds, Stab / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D017931:DNA Primers; D005904:Glial Fibrillary Acidic Protein; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma