Nuclear factor-kappaB activation in axons and Schwann cells in experimental sciatic nerve injury and its role in modulating axon regeneration: studies with etanercept.
Early inflammatory events may inhibit functional recovery after injury in both the peripheral and central nervous systems. We investigated the role of the inflammatory tumor necrosis factor/nuclear factor-kappaB (NF-kappaB) axis on events subsequent to sciatic nerve crush injury in adult rats. Electrophoretic mobility shift assays revealed that within 6 hours after crush, NF-kappaB DNA-binding activity increased significantly in a 1-cm section around the crush site. By immunofluorescence staining, there was increased nuclear localization of the NF-kappaB subunits p50 but not p65 or c-Rel in Schwann cells but no obvious inflammatory cell infiltration. In rats injected subcutaneously with etanercept, a tumor necrosis factor receptor chimera that binds free cytokine, the injury-induced rise in NF-kappaB DNA-binding activity was inhibited, and nuclear localization of p50 in Schwann cells was lowered after the injury. Axonal growth 3 days after nerve crush assessed with immunofluorescence for GAP43 demonstrated that the regeneration distance of leading axons from the site of nerve crush was greater in etanercept-treated animals than in saline-treated controls. These data indicate that tumor necrosis factor mediates rapid activation of injury-induced NF-kappaB DNA binding in Schwann cells and that these events are associated with inhibition of postinjury axonal sprouting.
Smith
Darrell
D
Division of Neurodegenerative Disorders, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada.
Tweed
Christopher
C
Fernyhough
Paul
P
Glazner
Gordon W
GW
D000818:Animals; D001369:Axons / Q000378:metabolism*; D019771:Axotomy / Q000379:methods; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D000068800:Etanercept; D019922:GAP-43 Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000627:therapeutic use*; D007211:Indoles; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D012583:Schwann Cells / Q000378:metabolism*; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
D019922:GAP-43 Protein; D007074:Immunoglobulin G; D007155:Immunologic Factors; D007211:Indoles; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D018124:Receptors, Tumor Necrosis Factor; C007293:DAPI; D000068800:Etanercept