Bilirubin-induced ER stress contributes to the inflammatory response and apoptosis in neuronal cells

Abstract

Unconjugated bilirubin (UCB) in newborns may lead to bilirubin neurotoxicity. Few studies investigated the activation of endoplasmic reticulum stress (ER stress) by UCB. We performed an in vitro comparative study using undifferentiated SH-SY5Y, differentiated GI-ME-N neuronal cells and human U87 astrocytoma cells. ER stress and its contribution to inflammation and apoptosis induced by UCB were analyzed. Cytotoxicity, ER stress and inflammation were observed only in neuronal cells, despite intracellular UCB accumulation in all three cell types. UCB toxicity was enhanced in undifferentiated SH-SY5Y cells and correlated with a higher mRNA expression of pro-apoptotic CHOP. Mouse embryonic fibroblast knockout for CHOP and CHOP siRNA-silenced SH-SY5Y increased cells viability upon UCB exposure. In SH-SY5Y, ER stress inhibition by 4-phenylbutyric acid reduced UCB-induced apoptosis and decreased the cleaved forms of caspase-3 and PARP proteins. Reporter gene assay and PERK siRNA showed that IL-8 induction by UCB is transcriptionally regulated by NFкB and PERK signaling. These data suggest that ER stress has an important role in the UCB-induced inflammation and apoptosis, and that targeting ER stress may represent a potential therapeutic approach to decrease UCB-induced neurotoxicity.

Induction of Mild Hyperbilirubinemia: Hype or Real Therapeutic Opportunity?

“…Moreover, bilirubin modulates cell signaling. Although toxic concentrations of bilirubin induce ER stress, milder elevations of bilirubin concentrations attenuate ER stress. Bilirubin was recently reported to act as a ligand for the peroxisome proliferator‐activated receptor‐alpha increasing its transcriptional activity .…”

Glutathione S-Transferase P1 Protects Against Amodiaquine Quinoneimines-Induced Cytotoxicity but Does Not Prevent Activation of Endoplasmic Reticulum Stress in HepG2 Cells

“…As shown in Figure 7 , AQ-QI and DEAQ-QI exposure resulted in activation of the ER stress response. Many chemicals have been reported to induce ER stress and subsequently cause toxicity in hepatic and extra-hepatic cells ( Fredriksson et al, 2014 ; Foufelle and Fromenty, 2016 ; Ren et al, 2016 ; Qaisiya et al, 2017 ), in particular chemically reactive benzoquinones which may react directly with ER proteins ( Wang et al, 2006 ; Kalinec et al, 2014 ). Mild ER stress assists cells with surviving from intrinsic or external insults.…”

Sorbents for Extracorporeal Removal of Toxic Substances and Molecules with Adverse Biological Activity (Review)

“…It is toxic for mitochondria at high concentrations, thus leading to disorders in the central nervous system [42]. It has been demon strated that the endoplasmic reticulum stress (ER stress) led to inflammatory reactions and apoptot ic death of neurons under the effect of excessive bilirubin concentrations [43]. Recent studies demonstrate high neurotoxicity of high bilirubin concentrations, at least, for nervous system cells including brain cells [44][45].…”

“…В очень высоких концентрациях он токсичен для митохондрий, что, в первую очередь, приводит к нарушениям на уровне ЦНС [42]. По казано, что возникающий под воздействием избы точных концентраций билирубина стресс эндо плазматической сети (ER стресс) приводил к провоспалительным реакциям и апоптотической гибели нейронов [43]. Недавние исследования сви детельствуют в пользу высокой нейротоксичности высокого содержания билирубина, по крайней ме ре, для клеток нервной системы, включая клетки мозга [44][45].…”