Blockade of Toll-like receptor 2 prevents spontaneous cytokine release from rheumatoid arthritis ex vivo synovial explant cultures.
Citation:
Ultaigh SN, Saber TP, McCormick J, Connolly M, Dellacasagrande J, Keogh B, McCormack W, Reilly M, O'Neill LA, McGuirk P, Fearon U, Veale DJ, Blockade of Toll-like receptor 2 prevents spontaneous cytokine release from rheumatoid arthritis ex vivo synovial explant cultures., Arthritis research & therapy, 13, 1, 2011, R33Download Item:

Abstract:
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
?
g/ml), an anti-TLR2 antibody (OPN301, 1
?
g/ml) or an immunoglobulin G (IgG) (1
?
g/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-
a
), IL-1
b
, IL-6,
interferon (IFN)-
g
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-
a
, IL-1
b
, IFN-
g
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-TNF
a
monoclonal antibody adalimumab.Conclusions:
These findings further support targeting TLR2 as a potential therapeutic agent for the treatment of RA.
Author's Homepage:
http://people.tcd.ie/laoneillDescription:
PUBLISHED
Author: O'NEILL, LUKE ANTHONY JOHN
Type of material:
Journal ArticleCollections:
Series/Report no:
Arthritis research & therapy13
1
Availability:
Full text availableKeywords:
monoclonal antibody adalimumabLicences: