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The Journal of Neuroscience, December 8, 2004, 24(49):11010-11016; doi:10.1523/JNEUROSCI.3823-04.2004

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Development/Plasticity/Repair
Tumor Necrosis Factor Receptor 1 and Its Signaling Intermediates Are Recruited to Lipid Rafts in the Traumatized Brain

George Lotocki,^2,3 Ofelia F. Alonso,^2,3 W. Dalton Dietrich,^2,3 and Robert W. Keane¹

Departments of ¹Physiology and Biophysics and ²Neurological Surgery, and ³Miami Project to Cure Paralysis, University of Miami School of Medicine, Miami, Florida 33136

The tumor necrosis factor (TNF) ligand-receptor system plays an essential role in apoptosis that contributes to secondary damage after traumatic brain injury (TBI). TNF also stimulates inflammation by activation of gene transcription through the IB kinase (IKK)/NF-B and JNK (c-Jun N-terminal protein kinase)/AP-1 signaling cascades. The mechanism by which TNF signals between cell death and survival and the role of receptor localization in the activation of downstream signaling events are not fully understood. Here, TNF receptor 1 (TNFR1) signaling complexes in lipid rafts were investigated in the cerebral cortex of adult male Sprague Dawley rats subjected to moderate (1.8-2.2 atmospheres) fluid-percussion TBI and naive controls. In the normal rat cortex, a portion of TNFR1 was present in lipid raft microdomains, where it associated with the adaptor proteins TRADD (TNF receptor-associated death domain), TNF receptor-associated factor-2 (TRAF-2), the Ser/Thr kinase RIP (receptor-interacting protein), TRAF1, and cIAP-1 (cellular inhibitor of apoptosis protein-1), forming a survival signaling complex. Moderate TBI resulted in rapid recruitment of TNFR1, but not TNFR2 or Fas, to lipid rafts and induced alterations in the composition of signaling intermediates. TNFR1 and TRAF1 were polyubiquitinated in lipid rafts after TBI. Subsequently, the signaling complex contained activated caspase-8, thus initiating apoptosis. In addition, TBI caused a transient activation of NF-B, but receptor signaling interacting proteins IKK and IKK were not detected in raft-containing fractions. Thus, redistribution of TNFR1 in lipid rafts and nonraft regions of the plasma membrane may regulate the diversity of signaling responses initiated by these receptors in the normal brain and after TBI.

Key words: tumor necrosis factor; apoptosis; traumatic brain injury; lipid rafts; intracellular signaling; inflammation

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Received July 22, 2004; revised October 29, 2004; accepted October 31, 2004.

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