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Advanced glycation end products‐related modulation of cathepsin L and NF‐κB signalling effectors in retinal pigment epithelium lead to augmented response to TNFα

The retinal pigment epithelium (RPE) plays a central role in neuroretinal homoeostasis throughout life. Altered proteolysis and inflammatory processes involving RPE contribute to the pathophysiology of age‐related macular degeneration (AMD), but the link between these remains elusive. We report for...

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Autores principales: Sharif, Umar, Mahmud, Nur Musfirah, Kay, Paul, Yang, Yit C., Harding, Simon P., Grierson, Ian, Kamalden, Tengku Ain, Jackson, Malcolm J., Paraoan, Luminita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307775/
https://www.ncbi.nlm.nih.gov/pubmed/30338926
http://dx.doi.org/10.1111/jcmm.13944
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author Sharif, Umar
Mahmud, Nur Musfirah
Kay, Paul
Yang, Yit C.
Harding, Simon P.
Grierson, Ian
Kamalden, Tengku Ain
Jackson, Malcolm J.
Paraoan, Luminita
author_facet Sharif, Umar
Mahmud, Nur Musfirah
Kay, Paul
Yang, Yit C.
Harding, Simon P.
Grierson, Ian
Kamalden, Tengku Ain
Jackson, Malcolm J.
Paraoan, Luminita
author_sort Sharif, Umar
collection PubMed
description The retinal pigment epithelium (RPE) plays a central role in neuroretinal homoeostasis throughout life. Altered proteolysis and inflammatory processes involving RPE contribute to the pathophysiology of age‐related macular degeneration (AMD), but the link between these remains elusive. We report for the first time the effect of advanced glycation end products (AGE)—known to accumulate on the ageing RPE's underlying Bruch's membrane in situ—on both key lysosomal cathepsins and NF‐κB signalling in RPE. Cathepsin L activity and NF‐κB effector levels decreased significantly following 2‐week AGE exposure. Chemical cathepsin L inhibition also decreased total p65 protein levels, indicating that AGE‐related change of NF‐κB effectors in RPE cells may be modulated by cathepsin L. However, upon TNFα stimulation, AGE‐exposed cells had significantly higher ratio of phospho‐p65(Ser536)/total p65 compared to non‐AGEd controls, with an even higher fold increase than in the presence of cathepsin L inhibition alone. Increased proportion of active p65 indicates an AGE‐related activation of NF‐κB signalling in a higher proportion of cells and/or an enhanced response to TNFα. Thus, NF‐κB signalling modulation in the AGEd environment, partially regulated via cathepsin L, is employed by RPE cells as a protective (para‐inflammatory) mechanism but renders them more responsive to pro‐inflammatory stimuli.
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spelling pubmed-63077752019-01-04 Advanced glycation end products‐related modulation of cathepsin L and NF‐κB signalling effectors in retinal pigment epithelium lead to augmented response to TNFα Sharif, Umar Mahmud, Nur Musfirah Kay, Paul Yang, Yit C. Harding, Simon P. Grierson, Ian Kamalden, Tengku Ain Jackson, Malcolm J. Paraoan, Luminita J Cell Mol Med Original Articles The retinal pigment epithelium (RPE) plays a central role in neuroretinal homoeostasis throughout life. Altered proteolysis and inflammatory processes involving RPE contribute to the pathophysiology of age‐related macular degeneration (AMD), but the link between these remains elusive. We report for the first time the effect of advanced glycation end products (AGE)—known to accumulate on the ageing RPE's underlying Bruch's membrane in situ—on both key lysosomal cathepsins and NF‐κB signalling in RPE. Cathepsin L activity and NF‐κB effector levels decreased significantly following 2‐week AGE exposure. Chemical cathepsin L inhibition also decreased total p65 protein levels, indicating that AGE‐related change of NF‐κB effectors in RPE cells may be modulated by cathepsin L. However, upon TNFα stimulation, AGE‐exposed cells had significantly higher ratio of phospho‐p65(Ser536)/total p65 compared to non‐AGEd controls, with an even higher fold increase than in the presence of cathepsin L inhibition alone. Increased proportion of active p65 indicates an AGE‐related activation of NF‐κB signalling in a higher proportion of cells and/or an enhanced response to TNFα. Thus, NF‐κB signalling modulation in the AGEd environment, partially regulated via cathepsin L, is employed by RPE cells as a protective (para‐inflammatory) mechanism but renders them more responsive to pro‐inflammatory stimuli. John Wiley and Sons Inc. 2018-10-19 2019-01 /pmc/articles/PMC6307775/ /pubmed/30338926 http://dx.doi.org/10.1111/jcmm.13944 Text en © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Sharif, Umar
Mahmud, Nur Musfirah
Kay, Paul
Yang, Yit C.
Harding, Simon P.
Grierson, Ian
Kamalden, Tengku Ain
Jackson, Malcolm J.
Paraoan, Luminita
Advanced glycation end products‐related modulation of cathepsin L and NF‐κB signalling effectors in retinal pigment epithelium lead to augmented response to TNFα
title Advanced glycation end products‐related modulation of cathepsin L and NF‐κB signalling effectors in retinal pigment epithelium lead to augmented response to TNFα
title_full Advanced glycation end products‐related modulation of cathepsin L and NF‐κB signalling effectors in retinal pigment epithelium lead to augmented response to TNFα
title_fullStr Advanced glycation end products‐related modulation of cathepsin L and NF‐κB signalling effectors in retinal pigment epithelium lead to augmented response to TNFα
title_full_unstemmed Advanced glycation end products‐related modulation of cathepsin L and NF‐κB signalling effectors in retinal pigment epithelium lead to augmented response to TNFα
title_short Advanced glycation end products‐related modulation of cathepsin L and NF‐κB signalling effectors in retinal pigment epithelium lead to augmented response to TNFα
title_sort advanced glycation end products‐related modulation of cathepsin l and nf‐κb signalling effectors in retinal pigment epithelium lead to augmented response to tnfα
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307775/
https://www.ncbi.nlm.nih.gov/pubmed/30338926
http://dx.doi.org/10.1111/jcmm.13944
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