title: The pro-inflammatory role of high-mobility group box 1 protein (HMGB-1) in photoreceptors and retinal explants exposed to elevated pressure.
abstract: To determine the role of high-mobility group box 1 protein (HMGB-1) in cellular and tissue models of elevated pressure-induced neurodegeneration, regeneration, and inflammation. Mouse retinal photoreceptor-derived cells (661W) and retinal explants were incubated either under elevated pressure or in the presence of recombinant HMGB-1 (rHMGB-1) to investigate the mechanisms of response of photoreceptors. Immunohistochemistry, western blotting, and the quantitative real-time PCR were used to examine the expression levels of immunological factors (eg, HMGB-1, receptor for advanced glycation end products (RAGE)), Toll-like receptors 2 and 4 (TLR-2, TLR-4), apoptosis-related factors (eg, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated death promoter (Bad)) as well as cytokine expression (eg, tumor necrosis factor alpha (TNF-α), interleukin (IL)-4, IL-6, and vascular endothelial growth factor (VEGF)). The data revealed increased the expression of HMGB-1 and its receptors RAGE, TLR-2, and TLR-4, and TNF-α as well as pro-apoptotic factors (eg, Bad) as well as apoptosis in 661W cells exposed to elevated pressure. Co-cultivation of 661W cells with rHMGB-1 increased the expression levels of pro-apoptotic Bad and cleaved Caspase-3 resulting in apoptosis. Cytokine array studies revealed an increased release of TNF-α, IL-4, IL-6, and VEGF after incubation of 661W cells with rHMGB-1. Upregulation of HMGB-1, TLR-2, and RAGE as well as anti-apoptotic Bcl-2 expression levels was found in the retinal explants exposed to rHMGB-1 or elevated pressure. The results suggest that HMGB-1 promotes an inflammatory response and mediates apoptosis in the pathology of photoreceptors and retinal homeostasis. HMGB-1 may have a key role in ongoing damage of retinal cells under conditions of elevated intraocular pressure.
authors.affiliation: Institute of Experimental Ophthalmology, School of Medicine, Westfalian-Wilhelms-University of Münster, Münster, Germany.|Department of Ophthalmology, St Franziskus Hospital Münster, Münster, Germany.
authors.forename: Michael R R
authors.initials: MR
authors.lastname: Böhm
authors.affiliation: Institute of Experimental Ophthalmology, School of Medicine, Westfalian-Wilhelms-University of Münster, Münster, Germany.|Department of Ophthalmology, University Hospital Essen, Essen, Germany.
authors.forename: Maurice
authors.initials: M
authors.lastname: Schallenberg
authors.affiliation: Institute of Experimental Ophthalmology, School of Medicine, Westfalian-Wilhelms-University of Münster, Münster, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Brockhaus
authors.affiliation: Institute of Experimental Ophthalmology, School of Medicine, Westfalian-Wilhelms-University of Münster, Münster, Germany.
authors.forename: Harutyun
authors.initials: H
authors.lastname: Melkonyan
authors.affiliation: Institute of Experimental Ophthalmology, School of Medicine, Westfalian-Wilhelms-University of Münster, Münster, Germany.|Cluster of Excellence 'Cells in Motion, CiM', Münster, Germany.
authors.forename: Solon
authors.initials: S
authors.lastname: Thanos
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D011312:Pressure; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology*; D012160:Retina / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046509:Tissue Culture Techniques; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: C000593873:Ager protein, mouse; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D011994:Recombinant Proteins; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4