TRAIL induces death of human oligodendrocytes isolated from adult brain

Abstract

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to induce apoptosis in various tumour cell lines and, recently, also in normal cells. TRAIL interacts with four receptors: two signalling receptors (TRAIL-R1 and TRAIL-R2) and two decoy receptors (TRAIL-R3 and TRAIL-R4). We have shown that both signalling receptors are present on the surface of oligodendrocytes isolated from adult human brain (ahOL), whereas the decoy receptors are expressed at a low level on ahOL. TRAIL induces ahOL apoptosis--as characterized by Annexin V staining prior to propidium iodide cell uptake--under conditions of protein synthesis inhibition. However, pre-treatment of ahOL with interferon gamma (IFNgamma) evoked susceptibility to TRAIL-induced death, which did not require inhibition of protein synthesis. A blocking experiment with monoclonal antibodies directed against TRAIL-R1 and TRAIL-R2 revealed that TRAIL-R1 is mainly involved in TRAIL-induced apoptosis of ahOL. In contrast to ahOL, microglial cells were completely resistant to cell death induced by TRAIL. Microglial cells had high surface expression of the decoy receptor TRAIL-R3, suggesting that resistance of these glial cells to TRAIL-induced death depends on the presence of the protective effect of TRAIL-R3. Stimulation of microglia with TRAIL increased further expression of TRAIL-R3, but it had no effect on the expression of TRAIL receptors by ahOL. This result may implicate TRAIL as an effector-immune molecule in selective ahOL demise in inflammatory/demyelinating conditions.

Protective effects of estradiol on TRAIL-induced apoptosis in a human oligodendrocytic cell line: evidence for multiple sites of interactions

“…In line with previous data, 28 Reverse transcriptase-PCR (RT-PCR) analysis for mRNAs and Western blot analysis for proteins showed that MO3.13 cells express both DR4 and DR5 receptors (Figure 1a and b). In the experiments, HeLa cell samples were used as internal positive controls.…”

“…As TRAIL represents a substantial cause of oligodendrocyte death, 28 in order to confirm specificity of such effect, we first studied whether the MO3.13 cell line expressed the two TRAIL receptors DR4 and DR5. In line with previous data, 28 Reverse transcriptase-PCR (RT-PCR) analysis for mRNAs and Western blot analysis for proteins showed that MO3.13 cells express both DR4 and DR5 receptors (Figure 1a and b).…”

“…In the experiments, HeLa cell samples were used as internal positive controls. 28 In further experiments, we evaluated the cytotoxic effect of TRAIL by adding 100 ng/ml of the cytokine to MO3.13 cell cultures. This concentration of TRAIL is known to induce cell death in most in vitro systems.…”

“…27 In support of these data, others have shown that estradiol is able to prevent TRAIL-induced HeLA cell death through the prevention of reactive oxygen species production and inhibition of the p38 kinase. 27 Matysiak et al 28 recently showed that human primary oligodendrocytes from human brain surgery ex vivo expressed TRAIL receptors and their exposure to TRAIL in vitro eventually resulted in cell death.…”

Fn14-TRAIL, a Chimeric Intercellular Signal Exchanger, Attenuates Experimental Autoimmune Encephalomyelitis

“…55 Thus, by combining the two, one has a single agent that could in principle impact both priming and later phases of the disease. 4) One group has reported that TRAIL may contribute to death of neurons after the priming phase, 70,73 in keeping with previous studies showing that both primary human neurons 74 and oligodendrocytes 75 are susceptible to TRAIL-induced cell death. By coupling Fn14 to TRAIL, one is providing an agent that sustains the integrity of the BBB (via TWEAK blockade) and thereby mitigates TRAIL's access to the CNS.…”