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.