Transforming growth factor-beta 1-mediated neuroprotection against excitotoxic injury in vivo.
Ischemic preconditioning is a phenomenon that describes how a sublethal ischemic insult can induce tolerance to subsequent ischemia. This phenomenon has been observed after focal or global ischemia in different animal models. However, the hypothesis that bacterial infection might lead to neuronal tolerance to injury has not been investigated. To mimic cerebral bacterial infection, we injected bacterial lipopolysaccharide (LPS) in the right dorsal hippocampus, followed 24 hours later by an excitotoxic lesion using kainic acid in the mouse model. Quantification of lesion size after cresyl violet counterstaining revealed that LPS pretreatment afforded neuroprotection to CA3 neurons against KA challenge. To investigate the events underlying this protection, we studied the cytokine profile induced after LPS injection. Interleukin (IL)-1 beta and transforming growth factor beta 1 (TGF-beta 1) were the main cytokines expressed at 24 hours after LPS injection. Because IL-1 beta has been described as deleterious in acute injury, we decided to investigate the function of TGF-beta 1. An adenovirus expressing a constitutively active form of TGF-beta 1 was injected intracerebrally 1 week before the induction of excitotoxic lesion, and neuronal protection was observed. To confirm the neuroprotective role of TGF-beta 1, the TGF-beta 1 adenovirus was replaced by recombinant human TGF-beta 1 protein and total neuroprotection was observed. Furthermore, the antibody-mediated blocking of TGF-beta 1 action prevented the protective effect of pretreatment with LPS. We have demonstrated in vivo that the cerebral tolerance phenomenon induced by LPS pretreatment is mediated by TGF-beta 1 cytokine.
Boche
Delphine
D
CNS Inflammation Group, Southampton Neuroscience Group, School of Biological Sciences, University of Southampton, Southampton, Hampshire, UK. D.Boche@soton.ac.uk
Cunningham
Colm
C
Gauldie
Jack
J
Perry
V Hugh
VH
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D016207:Cytokines / Q000096:biosynthesis; D018690:Excitatory Amino Acid Agonists; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D019194:Ischemic Preconditioning; D007608:Kainic Acid; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D016207:Cytokines; D018690:Excitatory Amino Acid Agonists; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D009498:Neurotoxins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D007608:Kainic Acid