title: IL-1β potently stabilizes IL-6 mRNA in human astrocytes.
abstract: Uncontrolled expression of IL-6 in the central nervous system is associated with neurodegenerative pathology and glioma development. Astrocytes are the predominant source of IL-6 in the central nervous system, and they are characteristically susceptible to synergistic IL-6 expression. Combined β-adrenergic and TNF-receptor triggering induces synergistic IL-6 expression in 1321N1 cells via a transcriptional enhancer mechanism. Here, we have investigated the molecular basis of the very potent "super"-synergistic IL-6 expression that is apparent after combined treatment of astrocytes with a β-adrenergic agonist, isoproterenol, and the inflammatory cytokines TNF-α and IL-1β. We found that IL-1β treatment strengthens the IL-6 synergy by inducing a distinct stabilization of IL-6 mRNA. Surprisingly, the mRNA-stabilizing effect seems to be dependent on protein kinase C (PKC), but not on the prototypical mRNA-stabilizing kinase p38. Moreover, although the mRNA-binding protein HuR basally stabilizes IL-6 mRNA, the mRNA-stabilizing effect of IL-1β is independent of HuR. Our data using pharmacological inhibitors suggest PKC is an important modulator of IL-6 expression in the central nervous system and this might have therapeutic implications.
authors.affiliation: Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST), University of Ghent, K.L. Ledeganckstraat 35, 9000 Ghent, Belgium.
authors.forename: Anneleen
authors.initials: A
authors.lastname: Spooren
authors.forename: Pieter
authors.initials: P
authors.lastname: Mestdagh
authors.forename: Pieter
authors.initials: P
authors.lastname: Rondou
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kolmus
authors.forename: Guy
authors.initials: G
authors.lastname: Haegeman
authors.forename: Sarah
authors.initials: S
authors.lastname: Gerlo
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002460:Cell Line; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D017930:Genes, Reporter; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D007545:Isoproterenol / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D053583:Interleukin-1beta; D015850:Interleukin-6; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D011493:Protein Kinase C; D007545:Isoproterenol