Zusammenfassung
Objective: In chronic inflammation, prevention of cAMP degradation by phosphodiesterase-4 (PDE4) inhibition can be anti-inflammatory therapy. However, PDE4 inhibition was uneffective in rheumatoid arthritis (RA). Recent studies demonstrated that PDE4/beta-arrestin interaction at beta-adrenoceptors resulted in switching from G alpha s to G alpha i signaling and ERK1/2 activation. Such a switch in ...
Zusammenfassung
Objective: In chronic inflammation, prevention of cAMP degradation by phosphodiesterase-4 (PDE4) inhibition can be anti-inflammatory therapy. However, PDE4 inhibition was uneffective in rheumatoid arthritis (RA). Recent studies demonstrated that PDE4/beta-arrestin interaction at beta-adrenoceptors resulted in switching from G alpha s to G alpha i signaling and ERK1/2 activation. Such a switch in signaling might elicit proinflammatory effects. We aimed to investigate this possible G alpha s to G alpha i signaling switch in RA and osteoarthritis (OA) mixed synoviocytes. Methods: Synoviocytes were treated alone or with combinations of adrenergic, dopaminergic, and adenosinergic drugs, rolipram (PDE4 inhibitor), inhibitors of G alpha i signaling (pertussis toxin), and blockers of protein kinase A (PI(A). Under normoxic or hypoxic conditions, proinflammatory TNF was the readout-parameter. We investigated co-expression and interaction of PDE4 and beta-arrestin by imaging techniques. Expression of pERK1/2 was analyzed by western blotting. Results: Mixed synoviocytes in RA and OA possessed all major G alpha s-coupled neurotransmitter receptors. Under hypoxia, particularly in RA cells, G alpha s-coupled receptor agonists unexpectedly increased TNF and respective antagonists decreased TNF. Under hypoxia, rolipram alone or rolipram plus G alpha s agonists increased TNF, which was reversed by pertussis toxin or PKA inhibition. Co-localization and interaction of PDE4 and beta-arrestin in synovial tissue and cells was demonstrated. G alpha s agonists or rolipram plus G alpha s agonists increased pERK1/2 expression. Conclusions: This study in human arthritic synovial tissue presents an unexpected proinflammatory switch from G alpha s to G alpha i signaling, which depends on PDE4/beta-arrestin interaction. This phenomenon is most probably responsible for reduced efficacy of PDE4 inhibitors and G alpha s agonists in RA. (C) 2015 Elsevier Inc. All rights reserved.
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