title: Therapeutic hypothermia modulates TNFR1 signaling in the traumatized brain via early transient activation of the JNK pathway and suppression of XIAP cleavage.
abstract: Tumor necrosis factor (TNF) plays a critical role in pathomechanisms associated with secondary damage after traumatic brain injury (TBI). The TNF ligand-receptor system stimulates inflammation by activation of gene transcription through the IkappaB kinase (IKK)-NF-kappaB and c-Jun NH(2)-terminal kinase (JNK)-AP-1 signaling cascades. TNF signaling following TBI involves both cell survival and apoptotic pathways, but the mechanism that accounts for the dual role of TNF remains unclear. Multiple studies have reported hypothermia to be protective following TBI, but the precise mechanism has not been clearly defined. Here, TNFR1 signaling pathways were investigated in the cerebral cortex of adult male Sprague-Dawley rats subjected to moderate fluid-percussion TBI and of naïve controls. Another group was subjected to moderate TBI with 30 min of pre- and post-traumatic hypothermia (33 degrees C). Rapid and marked increases in protein expression of TNFR1 and signaling intermediates in both the IKK-NF-kappaB and JNK pathways were induced in traumatized cortices. Hypothermia decreased TNFR1 protein expression acutely in traumatized cortices and stimulated early activation of signaling intermediates in the JNK, but not the IKK-NF-kappaB, signaling pathways. Hypothermia promoted a rapid activation of caspase-3 acutely after injury but suppressed caspase-3 activation at later time points. Moreover, hypothermia treatment suppressed cleavage of X-linked inhibitor of apoptosis protein (XIAP) into fragments induced by TBI. These data suggest that hypothermia may regulate both the JNK signaling cascade via XIAP and the preconditioning pathways that activate caspases. Thus, hypothermia mediates TNFR1 responses via early activation of the JNK signaling pathway and caspase-3, leading to endogenous neuroprotective events.
authors.affiliation: Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA.
authors.forename: George
authors.initials: G
authors.lastname: Lotocki
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: de Rivero Vaccari
authors.forename: Enrique R
authors.initials: ER
authors.lastname: Perez
authors.forename: Ofelia F
authors.initials: OF
authors.lastname: Alonso
authors.forename: Karell
authors.initials: K
authors.lastname: Curbelo
authors.forename: Robert W
authors.initials: RW
authors.lastname: Keane
authors.forename: W Dalton
authors.initials: WD
authors.lastname: Dietrich
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry; D001831:Body Temperature / Q000502:physiology; D001930:Brain Injuries / Q000503:physiopathology*; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D007036:Hypothermia, Induced; D020672:I-kappa B Proteins / Q000502:physiology; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D051381:Rats; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000502:physiology*
chemical_list: D000906:Antibodies; D018840:HSP70 Heat-Shock Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D051636:X-Linked Inhibitor of Apoptosis Protein; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases