IFNgamma enhances microglial reactions to hippocampal axonal degeneration.
Glial reactivity is implicated in CNS repair and regenerative responses. Microglia, the cells responding earliest to axonal injury, produce tumor necrosis factor-alpha (TNFalpha), a cytokine with both cytopathic and neuroprotective effects. We have studied activation of hippocampal microglia to produce TNFalpha in response to transection of perforant path axons in SJL/J mice. TNFalpha mRNA was produced in a transient manner, peaking at 2 d and falling again by 5 d after lesioning. This was unlike other markers of glial reactivity, such as Mac-1 upregulation, which were sustained over longer time periods. Message for the immune cytokine interferon-gamma (IFNgamma) was undetectable, and glial reactivity to axonal lesions occurred as normal in IFNgamma-deficient mice. Microglial responses to lesion-induced neuronal injury were markedly enhanced in myelin basic protein promoter-driven transgenic mice, in which IFNgamma was endogenously produced in hippocampus. The kinetics of TNFalpha downregulation 5 d after lesion was not affected by transgenic IFNgamma, indicating that IFNgamma acts as an amplifier and not an inducer of response. These results are discussed in the context of a regenerative role for TNFalpha in the CNS, which is innately regulated and potentiated by IFNgamma.
Jensen
M B
MB
Department of Anatomy and Neurobiology, University of Southern Denmark/Odense University, Odense C, DK 5000 Denmark.
Hegelund
I V
IV
Lomholt
N D
ND
Finsen
B
B
Owens
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001369:Axons / Q000473:pathology*; D003714:Denervation; D015870:Gene Expression / Q000276:immunology; D006624:Hippocampus / Q000473:pathology*; D017403:In Situ Hybridization; D007371:Interferon-gamma / Q000494:pharmacology*; D016177:Macrophage-1 Antigen / Q000032:analysis / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D004676:Myelin Basic Protein / Q000235:genetics; D009410:Nerve Degeneration / Q000276:immunology / Q000473:pathology; D009836:Oligodendroglia / Q000502:physiology; D019580:Perforant Pathway / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000276:immunology
D000970:Antineoplastic Agents; D016177:Macrophage-1 Antigen; D004676:Myelin Basic Protein; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma