Abstract
In rheumatoid arthritis, glucocorticoid secretion in relation to inflammation is inadequate. Besides their direct effects on inflammation, glucocorticoids induce indirect effects by modulation of the endocannabinoid system. Therefore, we hypothesize that some actions of cortisol in the periphery are also mediated by the endocannabinoid system. We inhibited FAAH, the major enzyme for endocannabinoid degradation, and blocked cannabinoid receptors (CBrs) to study the role of endocannabinoids in cortisol-mediated effects. We performed immunofluorescence analysis to detect all components of the endocannabinoid system in synovial fibroblasts (SFs). Adhesion was assessed using the Xcelligence system by Roche. Mass spectrometry was used to detect anandamide in tissue culture supernatants. Cortisol increased the adhesion of synovial fibroblasts to fibronectin in a dose dependent manner with a maximum at 10–8 M. This increase was blocked by a CB1r and a GPR18 antagonist but also by an inhibitor of FAAH. The latter effect could be reversed in SFs from osteoarthritic (OA) patients by nimesulide, a selective cox-2 inhibitor and O-1918, a GPR18 antagonist. The effect of cortisol on SF adhesion is dependent on the production and degradation of anandamide. This endocannabinoid binds a plethora of receptors, but all with different affinities. Due to FAAH inhibition, anandamide concentrations are altered within the cytoplasm. This might shift the cellular response from one receptor type to another explaining the observed effects.
Published Version
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