TNFR1 upregulation mediates tolerance after brain ischemic preconditioning.
A short ischemic event (ischemic preconditioning (IPC)) can result in subsequent resistance to severe ischemic injury (ischemic tolerance (IT)). The expression and neuroprotective role of tumor necrosis factor (TNF-alpha) have been described in models of IPC and we have showed the participation of its processing enzyme, the TNF-alpha convertase enzyme (TACE) in this process. We have now decided to explore the expression and localization of TNF receptors (TNFR) as well as other signalling mechanisms involved in IT. A period of 10 mins of temporary middle cerebral artery occlusion (tMCAO) was used for focal IPC. To evaluate the ability of IPC to produce IT, permanent MCAO was performed 48 hours after IPC. Ischemic preconditioning produced a reduction in infarct volume, as we showed previously. Ischemic preconditioning caused upregulation of neuronal TNFR1 that was reduced by the selective TACE inhibitor BB1101. Intracerebral administration of TNFR1 antisense oligodeoxynucleotide, which caused a reduction in TNFR1 expression, inhibited the IPC-induced protective effect, showing that TNFR1 upregulation is implicated in IT. Moreover, treatment with BB1101, TNFR1 antisense and lactacystin-a specific proteasome inhibitor-blocked IPC-induced NF-kappaB. Immunohistochemical studies showed the expression of TACE and TNFR1 in neurons. In summary, these data show that IPC produces neuronal upregulation of TACE and TNFR1, and that the pathway TACE/TNF-alpha/TNFR1/NF-kappaB is involved in IT.
Pradillo
Jesús M
JM
Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, Spain.
Romera
Cristina
C
Hurtado
Olivia
O
Cárdenas
Antonio
A
Moro
María A
MA
Leza
Juan C
JC
Dávalos
Antoni
A
Castillo
José
J
Lorenzo
Pedro
P
Lizasoain
Ignacio
I
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply*; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D019194:Ischemic Preconditioning; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606464:Adam17 protein, rat