title: IL-1β induces IL-6 production in retinal Müller cells predominantly through the activation of p38 MAPK/NF-κB signaling pathway.
abstract: IL-6 plays an important role in various inflammatory ocular diseases, including diabetic retinopathy. Müller cells are the major source of inflammatory mediators, including IL-6, in the retina. However, the mechanism of regulating IL-6 production in these cells remains unclear. Examination of signaling pathways in human retinal Müller cells (MIO-M1 cell line) cultured with IL-1β, TNF-α, IL-6, IL-8, VEGF, IFN-γ, glucose or mannitol showed that IL-1β was the most potent stimulator of IL-6 production. In addition, IL-1 β also increased NF-κB p50 protein level and phosphorylation of p38 MAPK, ERK1/2 and c-Jun. Induction of IL-6 production by IL-1β was significantly reduced by addition of p38 MAPK (SB203580), MEK1/2 (U0126) or NF-κB (BAY11-7082) inhibitors, with the highest effect being observed with SB203580. To explore the specific elements in IL-6 promoter responsible for IL-1β-induction of IL-6 expression, a series of plasmids bearing various IL-6 promoter mutations were transiently expressed in MIO-MI cells cultured in the presence or absence of IL-1β (10ng/ml) and/or SB203580 (10µM). Results showed that IL-6 promoter activity of the parent pIL-6-Luc651 was significantly enhanced by IL-1β, but the level was significantly attenuated by SB203580. Furthermore, the IL-6 promoter activity was also reduced upon deletion of NF-κB, AP-1 or C/EBP binding sites, with NF-κB deletion being the greatest. These results are the first demonstration that IL-1β induces IL-6 production in Müller cells by activation of IL-6 promoter activity predominantly through the p38 MAPK/NF-κB pathway.
authors.affiliation: Department of Ophthalmology, The First Hospital, Jilin University, Xinmin Street 71, Changchun, Jilin 130021, China.
authors.forename: Xiufen
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Huabao
authors.initials: H
authors.lastname: Xiong
authors.affiliation: Tissue Culture Center, New York Eye and Ear Infirmary of Mount Sinai, New York, NY 10003, USA.
authors.forename: Dan-Ning
authors.initials: DN
authors.lastname: Hu
authors.affiliation: Division of Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, Bath Street, London EC1V 9EL, UK.
authors.forename: G Astrid
authors.initials: GA
authors.lastname: Limb
authors.affiliation: Department of neurosurgery, The People׳s Hospital of Jilin Province, Changchun, Jilin 130021.
authors.forename: Tian
authors.initials: T
authors.lastname: Xie
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
authors.affiliation: Department of Medicine, Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Pili
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Wiley
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wu
authors.affiliation: Departments of Pathology, Urology, NYU Cancer Institute, New York Harbor Healthcare System, New York University, School of Medicine, New York, NY 10010, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Lee
authors.affiliation: Department of Ophthalmology, The First Hospital, Jilin University, Xinmin Street 71, Changchun, Jilin 130021, China; The Ophthalmology Hospital Affiliated Suzhou University, Jiangsu, Suzhou 215021, China. Electronic address: songe23@126.com.
authors.forename: E
authors.initials: E
authors.lastname: Song
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: david.zhang@mssm.edu.
authors.forename: David Y
authors.initials: DY
authors.lastname: Zhang
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012160:Retina / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D008156:Luciferases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Interleukin 1β (IL-1β); Interleukin 6 (IL-6); Müller cells; NF-κB; Promoter; p38 MAPK