title: 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.
authors: Fondazione Italiana Fegato ONLUS, Italian Liver Foundation ONLUS, AREA Science Park Basovizza Bldg Q, 34149, Trieste, Italy. m.qaisiya@csf.units.it.
authors: Mohammed
authors: M
authors: Qaisiya
authors: Fondazione Italiana Fegato ONLUS, Italian Liver Foundation ONLUS, AREA Science Park Basovizza Bldg Q, 34149, Trieste, Italy.
authors: Cristina
authors: C
authors: Brischetto
authors: Institute of Medical Biochemistry and Laboratory Medicine, 1st Faculty of Medicine, Charles University in Prague, 12000, Prague, Czech Republic.
authors: Jana
authors: J
authors: Jašprová
authors: Institute of Medical Biochemistry and Laboratory Medicine, 1st Faculty of Medicine, Charles University in Prague, 12000, Prague, Czech Republic.|4th Department of Internal Medicine, 1st Faculty of Medicine, Charles University in Prague, 12000, Prague, Czech Republic.
authors: Libor
authors: L
authors: Vitek
authors: Fondazione Italiana Fegato ONLUS, Italian Liver Foundation ONLUS, AREA Science Park Basovizza Bldg Q, 34149, Trieste, Italy.|Department of Medical Sciences, University of Trieste, 34149, Trieste, Italy.
authors: Claudio
authors: C
authors: Tiribelli
authors: Fondazione Italiana Fegato ONLUS, Italian Liver Foundation ONLUS, AREA Science Park Basovizza Bldg Q, 34149, Trieste, Italy.
authors: Cristina
authors: C
authors: Bellarosa
mesh_terms: D000818:Animals; D017209:Apoptosis; D001254:Astrocytoma / Q000378:metabolism; D001663:Bilirubin / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002470:Cell Survival; D059865:Endoplasmic Reticulum Stress; D020868:Gene Silencing; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010654:Phenylbutyrates / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000235:genetics*
chemical_list: D016209:Interleukin-8; D010654:Phenylbutyrates; D051742:Transcription Factor CHOP; C075773:4-phenylbutyric acid; D053148:Caspase 3; D001663:Bilirubin
keywords: 4-PBA; Bilirubin neurotoxicity; CHOP; ER stress; NFкB