title: Glycoursodeoxycholic acid and interleukin-10 modulate the reactivity of rat cortical astrocytes to unconjugated bilirubin.
abstract: The pathogenesis of bilirubin encephalopathy seems to result from accumulation of unconjugated bilirubin (UCB) within the brain. We have recently demonstrated that UCB causes astroglial release of proinflammatory cytokines and glutamate, as well as cell death. The bile acid glycoursodeoxycholic acid (GUDCA) and the anti-inflammatory cytokine interleukin (IL)-10 have been reported to modulate inflammation and cell survival. In this study we investigated the effect of these therapeutic agents on the astroglial response to UCB. Only GUDCA prevented UCB-induced astroglial death. The secretion of tumor necrosis factor-alpha (TNF-alpha) and IL-1beta elicited by UCB in astrocytes was reduced in the presence of GUDCA and IL-10, whereas the suppression of IL-6 was only counteracted by GUDCA. Neither GUDCA nor IL-10 modulated the accumulation of extracellular glutamate. Additionally, IL-10 markedly inhibited UCB-induced nuclear factor-kappaB nuclear translocation and cytokine mRNA expression, whereas GUDCA only prevented TNF-alpha mRNA expression. Moreover, GUDCA inhibited TNF-alpha- and IL-1beta-converting enzymes, preventing the maturation of these cytokines and their consequent release. Collectively, this study shows that IL-10 action is restricted to UCB-induced release of TNF-alpha and IL-1beta from the astrocytes, whereas GUDCA presents a more ubiquitous action on the astroglial reactivity to UCB. Hence, GUDCA may have potential benefits over an IL-10 therapeutic approach in reducing UCB-induced astrocyte immunostimulation and death.
authors.affiliation: Centro de Patogénese Molecular-Unidade de Biologia Molecular e Biopatologia Experimental, and Research Institute for Medicines and Pharmaceutical Sciences, Faculdade de Farmácia, University of Lisbon, Lisbon, Portugal.
authors.forename: Adelaide
authors.initials: A
authors.lastname: Fernandes
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Vaz
authors.forename: Ana S
authors.initials: AS
authors.lastname: Falcão
authors.forename: Rui F M
authors.initials: RF
authors.lastname: Silva
authors.forename: Maria A
authors.initials: MA
authors.lastname: Brito
authors.forename: Dora
authors.initials: D
authors.lastname: Brites
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors; D000072198:ADAM17 Protein; D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D001663:Bilirubin / Q000737:chemistry* / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D045604:Extracellular Fluid / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D016753:Interleukin-10 / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011498:Protein Precursors / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000093242:Interleukin-6 Inhibitors