Tumor Necrosis Factor Is a Brain Damaging Cytokine in Cerebral Ischemia

201

169

The inflammatory cytokines interleukin-1␤ and tumor necrosis factor-␣ (TNF-␣) have been identified as mediators of several forms of neurodegeneration in the brain. However, they can produce either deleterious or beneficial effects on neuronal function. We investigated the effects of these cytokines on neuronal death caused by exposure of mouse organotypic hippocampal slice cultures to toxic concentrations of AMPA. Either potentiation of excitotoxicity or neuroprotection was observed, depending on the concentration of the cytokines and the timing of exposure. A relatively high concentration of mouse recombinant TNF-␣ (10 ng/ml) enhanced excitotoxicity when the cultures were simultaneously exposed to AMPA and to this cytokine. Decreasing the concentration of TNF-␣ to 1 ng/ml resulted in neuroprotection against AMPA-induced neuronal death independently on the application protocol. By using TNF-␣ receptor (TNFR) knock-out mice, we demonstrated that the potentiation of AMPA-induced toxicity by TNF-␣ involves TNF receptor-1, whereas the neuroprotective effect is mediated by TNF receptor-2. AMPA exposure was associated with activation and proliferation of microglia as assessed by macrophage antigen-1 and bromodeoxyuridine immunohistochemistry, suggesting a functional recruitment of cytokineproducing cells at sites of neurodegeneration. Together, these findings are relevant for understanding the role of proinflammatory cytokines and microglia activation in acute and chronic excitotoxic conditions.

Section: Introductionmentioning

confidence: 99%

Modulator Effects of Interleukin-1β and Tumor Necrosis Factor-α on AMPA-Induced Excitotoxicity in Mouse Organotypic Hippocampal Slice Cultures

Bernardino¹,

Xapelli²,

Silva³

et al. 2005

201

169

“…The release of TNF␣ is upregulated by a variety of neuronal insults and disease states (New et al, 1998;Lock et al, 1999;Nagatsu et al, 2000;Perry et al, 2001), and preventing its signaling in vivo can, for example, prevent or reduce neuron loss after cerebral ischemia (Dawson et al, 1996;Barone et al, 1997;Meistrell et al, 1997) and head injury (for review, see Barone et al, 1997;Shohami et al, 1999). The pathological contributions of TNF␣ to neural injury are likely, at least in part, attributable to its ability to potentiate glutamate excitotoxicity (Gelbard et al, 1993;Chao and Hu, 1994;New et al, 1998;Epstein and Gelbard, 1999;Hermann et al, 2001), which importantly contributes to much of the secondary damage after brain insults (Choi, 1994;Wrathall et al, 1994).…”

mentioning

confidence: 99%

Differential Regulation of AMPA Receptor and GABA Receptor Trafficking by Tumor Necrosis Factor-α

Stellwagen¹,

Beattie²,

Seo³

et al. 2005

866

731

The proinflammatory cytokine tumor necrosis factor-␣ (TNF␣) causes a rapid exocytosis of AMPA receptors in hippocampal pyramidal cells and is constitutively required for the maintenance of normal surface expression of AMPA receptors. Here we demonstrate that TNF␣ acts on neuronal TNFR1 receptors to preferentially exocytose glutamate receptor 2-lacking AMPA receptors through a phosphatidylinositol 3 kinase-dependent process. This increases excitatory synaptic strength while changing the molecular stoichiometry of synaptic AMPA receptors. Conversely, TNF␣ causes an endocytosis of GABA A receptors, resulting in fewer surface GABA A receptors and a decrease in inhibitory synaptic strength. These results suggest that TNF␣ can regulate neuronal circuit homeostasis in a manner that may exacerbate excitotoxic damage resulting from neuronal insults.

“…TNF-␣ has been shown to potentiate the induction of neuronal apoptosis by HIV-1 Tat in primary human neurons (Shi et al, 1998), and has neurotoxic effects on primary human astrocytes because of its ability to inhibit glutamate uptake (Fine et al, 1996). In vivo studies have demonstrated damaging effects in cerebral ischemia (Dawson et al, 1996;Barone et al, 1997;Meistrell et al, 1997;Nawashiro et al, 1997), experimental autoimmune encephalomyelitis (Klinkert et al, 1997) and head injury models (Shohami et al, 1996(Shohami et al, , 1997. Furthermore, TNF-␣ contributes to apoptosis in rat hippocampal neurons during experimental meningitis (Bogdan et al, 1997).…”

mentioning

confidence: 99%

Reduction of Potassium Currents and Phosphatidylinositol 3-Kinase-Dependent Akt Phosphorylation by Tumor Necrosis Factor-α Rescues Axotomized Retinal Ganglion Cells from Retrograde Cell DeathIn Vivo

Diem¹,

Meyer²,

Weishaupt³

et al. 2001

132

Tumor-necrosis-factor-␣ (TNF-␣) prevented secondary death of retinal ganglion cells (RGCs) after axotomy of the optic nerve in vivo. This RGC rescue was confirmed in vitro in a mixed retinal culture model. In accordance with our previous findings, TNF-␣ decreased outward potassium currents in RGCs. Antagonism of the TNF-␣-induced decrease in outward potassium currents with the potassium channel opener minoxidilsulfate (as verified by electrophysiology) abolished neuroprotection. Western blot analysis revealed an upregulation of phospho-Akt as a consequence of TNF-␣-induced potassium current reduction. Inhibition of the phosphatidylinositol 3-kinase-Akt pathway with wortmannin decreased TNF-␣-promoted RGC survival. These data point to a functionally relevant cytokine-dependent neuroprotective signaling cascade in adult CNS neurons.