TY - JOUR
T1 - Target depletion of distinct tumor necrosis factor receptor subtypes reveals hippocampal neuron death and survival through different signal transduction pathways
AU - Yang, Libang
AU - Lindholm, Kristina
AU - Konishi, Yoshihiro
AU - Li, Rena
AU - Shen, Yong
PY - 2002/4/15
Y1 - 2002/4/15
N2 - 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.
AB - 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.
KW - NF-κB
KW - Neurodegeneration
KW - Neuronal survival
KW - TNF receptor
KW - TNF-α
KW - p38 MAP kinase
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UR - http://www.scopus.com/inward/citedby.url?scp=0037092420&partnerID=8YFLogxK
U2 - 10.1523/jneurosci.22-08-03025.2002
DO - 10.1523/jneurosci.22-08-03025.2002
M3 - Article
C2 - 11943805
AN - SCOPUS:0037092420
SN - 0270-6474
VL - 22
SP - 3025
EP - 3032
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 8
ER -