Therapeutic hypothermia modulates TNFR1 signaling in the traumatized brain via early transient activation of the JNK pathway and suppression of XIAP cleavage

George Lotocki, Juan Pablo P de Rivero Vaccari, Enrique R. Perez, Ofelia F. Alonso, Karell Curbelo, Robert Keane, W. Dalton Dietrich

Research output: Contribution to journalArticle

54 Citations (Scopus)

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 IκB kinase (IKK)-NF-κB 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°C). Rapid and marked increases in protein expression of TNFR1 and signaling intermediates in both the IKK-NF-κB 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-κB, 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.

Original languageEnglish
Pages (from-to)2283-2290
Number of pages8
JournalEuropean Journal of Neuroscience
Volume24
Issue number8
DOIs
StatePublished - Oct 1 2006

Fingerprint

X-Linked Inhibitor of Apoptosis Protein
Receptors, Tumor Necrosis Factor, Type I
Induced Hypothermia
Hypothermia
Phosphotransferases
Brain
Caspase 3
Tumor Necrosis Factor-alpha
Transcriptional Activation
Percussion
Tumor Necrosis Factor Receptors
Transcription Factor AP-1
Caspases
Cerebral Cortex
Sprague Dawley Rats
Traumatic Brain Injury
Cell Survival
Proteins
Ligands
Inflammation

Keywords

  • Apoptosis
  • Inflammation
  • Intracellular signaling
  • Preconditioning
  • Traumatic brain injury
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Therapeutic hypothermia modulates TNFR1 signaling in the traumatized brain via early transient activation of the JNK pathway and suppression of XIAP cleavage. / Lotocki, George; de Rivero Vaccari, Juan Pablo P; Perez, Enrique R.; Alonso, Ofelia F.; Curbelo, Karell; Keane, Robert; Dalton Dietrich, W.

In: European Journal of Neuroscience, Vol. 24, No. 8, 01.10.2006, p. 2283-2290.

Research output: Contribution to journalArticle

@article{691c6789f00443769102e6a77b4c948f,
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 IκB kinase (IKK)-NF-κB 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 na{\"i}ve controls. Another group was subjected to moderate TBI with 30 min of pre- and post-traumatic hypothermia (33°C). Rapid and marked increases in protein expression of TNFR1 and signaling intermediates in both the IKK-NF-κB 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-κB, 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.",
keywords = "Apoptosis, Inflammation, Intracellular signaling, Preconditioning, Traumatic brain injury, Tumor necrosis factor",
author = "George Lotocki and {de Rivero Vaccari}, {Juan Pablo P} and Perez, {Enrique R.} and Alonso, {Ofelia F.} and Karell Curbelo and Robert Keane and {Dalton Dietrich}, W.",
year = "2006",
month = "10",
day = "1",
doi = "10.1111/j.1460-9568.2006.05123.x",
language = "English",
volume = "24",
pages = "2283--2290",
journal = "European Journal of Neuroscience",
issn = "0953-816X",
publisher = "Wiley-Blackwell",
number = "8",

}

TY - JOUR

T1 - Therapeutic hypothermia modulates TNFR1 signaling in the traumatized brain via early transient activation of the JNK pathway and suppression of XIAP cleavage

AU - Lotocki, George

AU - de Rivero Vaccari, Juan Pablo P

AU - Perez, Enrique R.

AU - Alonso, Ofelia F.

AU - Curbelo, Karell

AU - Keane, Robert

AU - Dalton Dietrich, W.

PY - 2006/10/1

Y1 - 2006/10/1

N2 - 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 IκB kinase (IKK)-NF-κB 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°C). Rapid and marked increases in protein expression of TNFR1 and signaling intermediates in both the IKK-NF-κB 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-κB, 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.

AB - 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 IκB kinase (IKK)-NF-κB 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°C). Rapid and marked increases in protein expression of TNFR1 and signaling intermediates in both the IKK-NF-κB 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-κB, 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.

KW - Apoptosis

KW - Inflammation

KW - Intracellular signaling

KW - Preconditioning

KW - Traumatic brain injury

KW - Tumor necrosis factor

UR - http://www.scopus.com/inward/record.url?scp=33750349217&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33750349217&partnerID=8YFLogxK

U2 - 10.1111/j.1460-9568.2006.05123.x

DO - 10.1111/j.1460-9568.2006.05123.x

M3 - Article

VL - 24

SP - 2283

EP - 2290

JO - European Journal of Neuroscience

JF - European Journal of Neuroscience

SN - 0953-816X

IS - 8

ER -