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Blockade of Toll-like receptor 2 prevents spontaneous cytokine release from rheumatoid arthritis ex vivo synovial explant cultures

INTRODUCTION: The aim of this study was to examine the effect of blocking Toll-like receptor 2 (TLR2) in rheumatoid arthritis (RA) synovial cells. METHODS: RA synovial tissue biopsies, obtained under direct visualization at arthroscopy, were established as synovial explant cultures ex vivo or snap f...

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Autores principales: Nic An Ultaigh, Sinéad, Saber, Tajvur P, McCormick, Jennifer, Connolly, Mary, Dellacasagrande, Jerome, Keogh, Brian, McCormack, William, Reilly, Mary, O'Neill, Luke A, McGuirk, Peter, Fearon, Ursula, Veale, Douglas J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3241377/
https://www.ncbi.nlm.nih.gov/pubmed/21345222
http://dx.doi.org/10.1186/ar3261
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author Nic An Ultaigh, Sinéad
Saber, Tajvur P
McCormick, Jennifer
Connolly, Mary
Dellacasagrande, Jerome
Keogh, Brian
McCormack, William
Reilly, Mary
O'Neill, Luke A
McGuirk, Peter
Fearon, Ursula
Veale, Douglas J
author_facet Nic An Ultaigh, Sinéad
Saber, Tajvur P
McCormick, Jennifer
Connolly, Mary
Dellacasagrande, Jerome
Keogh, Brian
McCormack, William
Reilly, Mary
O'Neill, Luke A
McGuirk, Peter
Fearon, Ursula
Veale, Douglas J
author_sort Nic An Ultaigh, Sinéad
collection PubMed
description INTRODUCTION: The aim of this study was to examine the effect of blocking Toll-like receptor 2 (TLR2) in rheumatoid arthritis (RA) synovial cells. METHODS: RA synovial tissue biopsies, obtained under direct visualization at arthroscopy, were established as synovial explant cultures ex vivo or snap frozen for immunohistology. Mononuclear cell cultures were isolated from peripheral blood and synovial fluid of RA patients. Cultures were incubated with the TLR1/2 ligand, Pam3CSK4 (200 ng, 1 and 10 μg/ml), an anti-TLR2 antibody (OPN301, 1 μg/ml) or an immunoglobulin G (IgG) (1 μg/ml) matched control. The comparative effect of OPN301 and adalimumab (anti-tumour necrosis factor alpha) on spontaneous release of proinflammatory cytokines from RA synovial explants was determined using quantitative cytokine MSD multiplex assays or ELISA. OPN301 penetration into RA synovial tissue explants cultures was assessed by immunohistology. RESULTS: Pam3CSK4 significantly upregulated interleukin (IL)-6 and IL-8 in RA peripheral blood mononuclear cells (PBMCs), RA synovial fluid mononuclear cells (SFMCs) and RA synovial explant cultures (P < 0.05). OPN301 significantly decreased Pam3CSK4-induced cytokine production of tumour necrosis factor alpha (TNF-α), IL-1β, IL-6, interferon (IFN)-γ and IL-8 compared to IgG control in RA PBMCs and SFMCs cultures (all P < 0.05). OPN301 penetration of RA synovial tissue cultures was detected in the lining layer and perivascular regions. OPN301 significantly decreased spontaneous cytokine production of TNF-α, IL-1β, IFN-γ and IL-8 from RA synovial tissue explant cultures (all P < 0.05). Importantly, the inhibitory effect of OPN on spontaneous cytokine secretion was comparable to inhibition by anti-TNFα monoclonal antibody adalimumab. CONCLUSIONS: These findings further support targeting TLR2 as a potential therapeutic agent for the treatment of RA.
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spelling pubmed-32413772011-12-17 Blockade of Toll-like receptor 2 prevents spontaneous cytokine release from rheumatoid arthritis ex vivo synovial explant cultures Nic An Ultaigh, Sinéad Saber, Tajvur P McCormick, Jennifer Connolly, Mary Dellacasagrande, Jerome Keogh, Brian McCormack, William Reilly, Mary O'Neill, Luke A McGuirk, Peter Fearon, Ursula Veale, Douglas J Arthritis Res Ther Research Article INTRODUCTION: The aim of this study was to examine the effect of blocking Toll-like receptor 2 (TLR2) in rheumatoid arthritis (RA) synovial cells. METHODS: RA synovial tissue biopsies, obtained under direct visualization at arthroscopy, were established as synovial explant cultures ex vivo or snap frozen for immunohistology. Mononuclear cell cultures were isolated from peripheral blood and synovial fluid of RA patients. Cultures were incubated with the TLR1/2 ligand, Pam3CSK4 (200 ng, 1 and 10 μg/ml), an anti-TLR2 antibody (OPN301, 1 μg/ml) or an immunoglobulin G (IgG) (1 μg/ml) matched control. The comparative effect of OPN301 and adalimumab (anti-tumour necrosis factor alpha) on spontaneous release of proinflammatory cytokines from RA synovial explants was determined using quantitative cytokine MSD multiplex assays or ELISA. OPN301 penetration into RA synovial tissue explants cultures was assessed by immunohistology. RESULTS: Pam3CSK4 significantly upregulated interleukin (IL)-6 and IL-8 in RA peripheral blood mononuclear cells (PBMCs), RA synovial fluid mononuclear cells (SFMCs) and RA synovial explant cultures (P < 0.05). OPN301 significantly decreased Pam3CSK4-induced cytokine production of tumour necrosis factor alpha (TNF-α), IL-1β, IL-6, interferon (IFN)-γ and IL-8 compared to IgG control in RA PBMCs and SFMCs cultures (all P < 0.05). OPN301 penetration of RA synovial tissue cultures was detected in the lining layer and perivascular regions. OPN301 significantly decreased spontaneous cytokine production of TNF-α, IL-1β, IFN-γ and IL-8 from RA synovial tissue explant cultures (all P < 0.05). Importantly, the inhibitory effect of OPN on spontaneous cytokine secretion was comparable to inhibition by anti-TNFα monoclonal antibody adalimumab. CONCLUSIONS: These findings further support targeting TLR2 as a potential therapeutic agent for the treatment of RA. BioMed Central 2011 2011-02-23 /pmc/articles/PMC3241377/ /pubmed/21345222 http://dx.doi.org/10.1186/ar3261 Text en Copyright ©2011 Nic An Ultaigh et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Nic An Ultaigh, Sinéad
Saber, Tajvur P
McCormick, Jennifer
Connolly, Mary
Dellacasagrande, Jerome
Keogh, Brian
McCormack, William
Reilly, Mary
O'Neill, Luke A
McGuirk, Peter
Fearon, Ursula
Veale, Douglas J
Blockade of Toll-like receptor 2 prevents spontaneous cytokine release from rheumatoid arthritis ex vivo synovial explant cultures
title Blockade of Toll-like receptor 2 prevents spontaneous cytokine release from rheumatoid arthritis ex vivo synovial explant cultures
title_full Blockade of Toll-like receptor 2 prevents spontaneous cytokine release from rheumatoid arthritis ex vivo synovial explant cultures
title_fullStr Blockade of Toll-like receptor 2 prevents spontaneous cytokine release from rheumatoid arthritis ex vivo synovial explant cultures
title_full_unstemmed Blockade of Toll-like receptor 2 prevents spontaneous cytokine release from rheumatoid arthritis ex vivo synovial explant cultures
title_short Blockade of Toll-like receptor 2 prevents spontaneous cytokine release from rheumatoid arthritis ex vivo synovial explant cultures
title_sort blockade of toll-like receptor 2 prevents spontaneous cytokine release from rheumatoid arthritis ex vivo synovial explant cultures
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3241377/
https://www.ncbi.nlm.nih.gov/pubmed/21345222
http://dx.doi.org/10.1186/ar3261
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