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2015 ; 17
(ä): 321
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Anti-inflammatory effects of N-acylethanolamines in rheumatoid arthritis synovial
cells are mediated by TRPV1 and TRPA1 in a COX-2 dependent manner
#MMPMID26567045
Lowin T
; Apitz M
; Anders S
; Straub RH
Arthritis Res Ther
2015[Nov]; 17
(ä): 321
PMID26567045
show ga
INTRODUCTION: The endocannabinoid system modulates function of immune cells and
mesenchymal cells such as fibroblasts, which contribute to cartilage destruction
in rheumatoid arthritis (RA). The aim of the study was to determine the influence
of N-acylethanolamines anandamide (AEA), palmitoylethanolamine (PEA) and
oleylethanolamine (OEA) on several features of arthritic inflammation in vitro
(human material) and in vivo (a mouse model). METHODS: Immunofluorescence and
western blotting were used to detect cannabinoid receptors and related enzymes.
Cytokines and MMP-3 were measured by ELISA. Intracellular signaling proteins were
detected by proteome profiling. Proliferation was quantified by CTB reagent.
Adhesion was assessed by the xCELLigence system. After onset of collagen type II
arthritis, mice were treated daily with the FAAH inhibitor JNJ1661010 (20 mg/kg)
or vehicle. RESULTS: IL-6, IL-8 and MMP-3 (determined only in synovial
fibroblasts (SFs)) were downregulated in primary synoviocytes and SFs of RA and
OA after AEA, PEA and OEA treatment. In SFs, this was due to activation of TRPV1
and TRPA1 in a COX-2-dependent fashion. FAAH inhibition increased the efficacy of
AEA in primary synoviocytes but not in SFs. The effects of OEA and PEA on SFs
were diminished by FAAH inhibition. Adhesion to fibronectin was increased in a
CB1-dependent manner by AEA in OASFs. Furthermore, elevation of endocannabinoids
ameliorated collagen-induced arthritis in mice. CONCLUSIONS: N-acylethanolamines
exert anti-inflammatory effects in SFs. A dual FAAH/COX-2 inhibitor, increasing
N-acylethanolamine levels with concomitant TRP channel desensitization, might be
a good candidate to inhibit the production of proinflammatory mediators of
synovial cells and to reduce erosions.