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Tumor necrosis factor receptor-I (TNFRI) and TNFRII are two TNFR subtypes in the immune system, but their roles in the brain remain unclear. Here we present a novel interaction between TNFR subtypes and TNF-α in the brain. Our studies on target-depleted TNFR in mice show that TNF-α has little effect on hippocampal neurons in which TNFRI, containing an “intracellular death domain,” is absent (TNFRI −/−), whereas neurons from TNFRII knock-out mice are vulnerable to TNF-α even at low doses. Moreover, little nuclear factor-κB (NF-κB) translocation is induced by TNF-α in neurons of TNFRI −/−, whereas NF-κB subunit p65 is still translocated from the cytoplasm into the nucleus in neurons from wild-type and TNFRII −/− mice. Furthermore, p38 mitogen-activated protein (MAP) kinase activity is upregulated in neurons from both wild-type and TNFRI −/−, but no alteration of p38 MAP kinase was found in neurons from TNFRII. Results from overexpression of TNF receptors further support the above findings. NT2 neuronal-like cells transiently transfected with TNFRI are very sensitive to TNF-α, whereas TNF-α is not toxic and even seems to be trophic to the cells with TNFRII overexpression. Last, our radioligand-binding experiments demonstrate that TNF-α binds TNFRI with high affinity (Kd of 0.6 nm), whereas TNFRII shows lower binding affinity (Kd of 1.14 nm) to TNF-α in NT2 transfected cells. Together, these studies reveal novel neuronal responses of TNF-α in mediating consequences of TNF receptor activation differently. Subsequent neuronal death or survival may ultimately depend on a particular subtype of TNF receptor that is predominately expressed in neurons of the brain during neural development or with neurological diseases.

the journal of neuroscience/the journal of neuroscience

Target Depletion of Distinct Tumor Necrosis Factor Receptor Subtypes Reveals Hippocampal Neuron Death and Survival through Different Signal Transduction Pathways