title: Tumor necrosis factor in traumatic brain injury: effects of genetic deletion of p55 or p75 receptor.
abstract: The role of tumor necrosis factor (TNF) and its receptors after traumatic brain injury (TBI) remains unclear. We evaluated the effects of genetic deletion of either p55 or p75 TNF receptor on neurobehavioral outcome, histopathology, DNA damage and apoptosis-related cell death/survival gene expression (bcl-2/bax), and microglia/macrophage (M/M) activation in wild-type (WT) and knockout mice after TBI. Injured p55 (-/-) mice showed a significant attenuation while p75 (-/-) mice showed a significant worsening of sensorimotor deficits compared with WT mice over 4 weeks postinjury. At the same time point, contusion volume in p55 (-/-) mice (11.1±3.3 mm(3)) was significantly reduced compared with WT (19.7±3.4 mm(3)) and p75 (-/-) mice (20.9±3.2 mm(3)). At 4 hours postinjury, bcl-2/bax ratio mRNA expression was increased in p55 (-/-) compared with p75 (-/-) mice and was associated with reduced DNA damage terminal deoxynucleotidyl transferaseYmediated dUTP nick end labeling (TUNEL-positivity), reduced CD11b expression and increased Ym1 expression at 24 hours postinjury in p55 (-/-) compared with p75 (-/-) mice, indicative of a protective M/M response. These data suggest that TNF may exacerbate neurobehavioral deficits and tissue damage via p55 TNF receptor whose inhibition may represent a specific therapeutic target after TBI.
authors.affiliation: Department of Pathophysiology and Transplantation, Neurosurgical Intensive Care Unit, University of Milano, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Longhi
authors.forename: Carlo
authors.initials: C
authors.lastname: Perego
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Ortolano
authors.forename: Silvia
authors.initials: S
authors.lastname: Aresi
authors.forename: Stefano
authors.initials: S
authors.lastname: Fumagalli
authors.forename: Elisa R
authors.initials: ER
authors.lastname: Zanier
authors.forename: Nino
authors.initials: N
authors.lastname: Stocchetti
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: De Simoni
mesh_terms: D000465:Algorithms; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology; D001930:Brain Injuries / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000235:genetics; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D017353:Gene Deletion; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D011597:Psychomotor Performance / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics* / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics* / Q000378:metabolism*; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1