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

Authors

  • George Lotocki,

    1. Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
    2. Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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  • Juan Pablo De Rivero Vaccari,

    1. Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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  • Enrique R. Perez,

    1. Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
    2. Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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  • Ofelia F. Alonso,

    1. Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
    2. Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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  • Karell Curbelo,

    1. Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
    2. Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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  • Robert W. Keane,

    1. Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
    2. Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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  • W. Dalton Dietrich

    1. Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
    2. Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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Dr W. Dalton Dietrich, 1Department of Neurological Surgery, as above.
E-mail: ddietrich@miami.edu

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 NH2-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.

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