Background/Purpose

In recent studies, we confirmed the anti-inflammatory effects of tyrosine-hydroxylase (TH)-positive catecholamine producing synovial cells in chronic arthritis. Other studies described that inhibitors of the cAMP-degrading enzyme, phosphodiesterase 4 (PDE4), exhibit anti-inflammatory effects (see FDA-approved therapy with apremilast). Furthermore, Lefkowitz et al.¹ demonstrated that the interaction of PDE4 with β-arrestin at β-adrenoceptor can result in a catecholamine receptor switching from Gαs to Gαi signalling with subsequent ERK1/2 activation. Therefore, the aim of our study was to investigate whether and how PDE4 and catecholamine signaling interact and possibly influence inflammatory responses in chronic arthritis.

Methods

Immunostaining of PDE4 and β-arrestin and visualization of presumed PDE4/β-arrestin interaction (via proximity ligation assay) was performed in synovial tissue and in synovial cell culture of rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Synovial cells were cultivated under normoxic or hypoxic conditions (the microenvironment of inflamed joints is hypoxic) with/without PDE4 inhibitor and/or different concentrations of catecholamine receptor agonists, adenosine receptor agonists, and/or blocker of Gαi-mediated pathways (pertussis toxin, ERK1/2 blocker). After 24 hours, supernatants were collected, cytokine concentrations were determined, and activation of ERK1/2 signaling was analyzed.

Results

Both, PDE4 and β-arrestin were detected in the synovial tissue and in synovial cell culture of OA and RA patients. Moreover, the interaction of PDE4/β-arrestin was demonstrated with proximity ligation assay. Under hypoxia, Gαs-coupled adrenoceptor agonists decreased TNF release in both OA and RA synovial cell culture. In contrast to normoxia, hypoxic incubation with PDE4 inhibitor alone and co-incubation with PDE4 inhibitor and catecholamine receptor agonists with Gαs-protein pathway increased TNF release, which was reversed by pertussis toxin or by ERK1/2 blocker. Western blot analyses demonstrated an increased ERK1/2 activation after treatment with Gαs-coupled adrenoceptor agonist alone or after co-incubation with PDE4 inhibitor and Gαs-coupled adrenoceptor agonist.

Conclusion

In summary, this study presents that PDE4 and b-arrestin interact at catecholamine receptors in human arthritic synovial tissue inducing catecholamine receptor switching from Gαs to Gαi signalling, which results in the reversal of catecholamine-induced anti-inflammatory effects at high neurotransmitter concentrations. This phenomenon might be responsible for possible reduced efficacy of PDE4 inhibitor treatment in some chronic arthritic diseases.

1. Baillie GS, Lefkowitz RJ et al. Proc Natl Acad Sci U S A. 2003

 

 

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interaction-of-pde4-and-%ce%b2-arrestin-reverses-anti-inflammatory-effects-of-catecholamine-producing-cells-in-chronic-arthritis-via-adrenoceptor-switching-from-g%ce%b1s-to-g%ce%b1i-signalling/