Target depletion of distinct tumor necrosis factor receptor subtypes reveals hippocampal neuron death and survival through different signal transduction pathways

Libang Yang, Kristina Lindholm, Yoshihiro Konishi, Rena Li, Yong Shen

Research output: Contribution to journalArticle

196 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3025-3032
Number of pages8
JournalJournal of Neuroscience
Volume22
Issue number8
StatePublished - Apr 15 2002

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Keywords

  • NF-κB
  • Neurodegeneration
  • Neuronal survival
  • TNF receptor
  • TNF-α
  • p38 MAP kinase

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