Proinflammatory receptor switch from Gαs to Gαi signaling by β-arrestin-mediated PDE4 recruitment in mixed RA synovial cells.

摘要: Abstract Objective In chronic inflammation, prevention of cAMP degradation by phosphodiesterase-4 (PDE4) inhibition can be anti-inflammatory therapy. However, PDE4 was uneffective in rheumatoid arthritis (RA). Recent studies demonstrated that PDE4/β-arrestin interaction at β-adrenoceptors resulted switching from Gαs to Gαi signaling and ERK1/2 activation. Such a switch might elicit proinflammatory effects. We aimed investigate this possible RA osteoarthritis (OA) mixed synoviocytes. Methods Synoviocytes were treated alone or with combinations adrenergic, dopaminergic, adenosinergic drugs, rolipram (PDE4 inhibitor), inhibitors (pertussis toxin), blockers protein kinase A (PKA). Under normoxic hypoxic conditions, TNF the readout-parameter. investigated co-expression β-arrestin imaging techniques. Expression pERK1/2 analyzed western blotting. Results Mixed synoviocytes OA possessed all major Gαs-coupled neurotransmitter receptors. hypoxia, particularly cells, receptor agonists unexpectedly increased respective antagonists decreased TNF. plus TNF, which reversed pertussis toxin PKA inhibition. Co-localization synovial tissue cells demonstrated. expression. Conclusions This study human arthritic presents an unexpected signaling, depends on interaction. phenomenon is most probably responsible for reduced efficacy RA.