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

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-alpha in the brain. Our studies on target-depleted TNFR in mice show that TNF-alpha 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-alpha even at low doses. Moreover, little nuclear factor-kappaB (NF-kappaB) translocation is induced by TNF-alpha in neurons of TNFRI -/-, whereas NF-kappaB 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-alpha, whereas TNF-alpha is not toxic and even seems to be trophic to the cells with TNFRII overexpression. Last, our radioligand-binding experiments demonstrate that TNF-alpha binds TNFRI with high affinity (K(d) of 0.6 nm), whereas TNFRII shows lower binding affinity (K(d) of 1.14 nm) to TNF-alpha in NT2 transfected cells. Together, these studies reveal novel neuronal responses of TNF-alpha 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.

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

“…Its function in the pathogenesis of neural injury remains unclear, however, because both neurotoxic and neuroprotective effects after injury have been described (Bruce et al, 1996;Nawashiro et al, 1997;Kim et al, 2001;Martin-Villalba et al, 2001;Yang et al, 2002). Traumatic brain injury (TBI) induces upregulation of TNF-␣ protein and mRNA in the injured cortex (Taupin et al, 1993;Fan et al, 1996;Shohami et al, 1996Shohami et al, , 1997Vitarbo et al, 2004), and increased levels of TNF-␣ have been reported in plasma and CSF of head-injured patients (Ross et al, 1994).…”

Tumor Necrosis Factor α Regulates Responses to Nerve Growth Factor, Promoting Neural Cell Survival but Suppressing Differentiation of Neuroblastoma Cells

“…Although further experiments are required to clarify the mechanism controlling the receptor preference of TNF-␣, one possibility is that NGF-induced TNF-␣ activates both TNFR1 and TNFR2 but cooperation of NGF signaling and TNFR2 signaling antagonizes TNFR1-induced proapoptotic signals. In agreement with this, exogenously added TNF-␣ fails to induce sufficient neural cell death of cultured neurons in the presence of NGF (Barker et al, 2001), and signaling from TNFR2 can antagonize proapoptotic signals from TNFR1 (Yang et al, 2002). Therefore, NGF-induced TNF-␣ seems to be bifunctional; NGF-induced TNF-␣ has a major role in the NGF-dependent survival of neurons, but once NGF is withdrawn, the TNF-␣ contributes to neuron killing.…”

“…Knockdown of TNFR2 sensitizes a neuroblastoma cell line to cell death initiated by ␤-amyloid (Shen et al, 1997). Hippocampal neurons isolated from TNFR2-deficient mice are more sensitive to TNF-␣-induced cell death than the neurons from normal mice (Yang et al, 2002). Furthermore, TNFR2 signaling is required for both survival of retinal neurons from ischemia-reperfusion (Fontaine et al, 2002) and survival of cortical neurons from glutamate-induced excitotoxicity (Marchetti et al, 2004).…”

Role of tumour necrosis factor (TNF)-α and TNFRSF1A R92Q mutation in the pathogenesis of TNF receptor-associated periodic syndrome and multiple sclerosis

“…Such signals lead to the activation of NF-kB, promoting tissue survival, although in some cases the receptor could also collaborate with its counterpart, contributing to cell death [14]. Although the activa- Tumour necrosis factor receptor 1 (TNFR1) and its signalling pathways.…”