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43. Kongress der Deutschen Gesellschaft für Rheumatologie, 29. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie, 25. Wissenschaftliche Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie

02.-05. September 2015, Bremen

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Proinflammatory receptor switch from Gαs to Gαi signaling in mixed RA synovial cells caused by the interaction of PDE4 and β-arrestin

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  • Zsuzsa Jenei-Lanzl - Universitätsklinikum Regensburg, Klinik und Poliklinik für Innere Medizin I, Rheumatologie und Klinische Immunologie, Regensburg
  • Janika Zwingenberg - Innere Med I, Universitätsklinikum Regensburg, Regensburg
  • Torsten Lowin - Innere Med I, Universitätsklinikum Regensburg, Regensburg
  • Sven Anders - Innere Med I, Universitätsklinikum Regensburg, Regensburg
  • Rainer H. Straub - Innere Med I, Universitätsklinikum Regensburg, Regensburg

Deutsche Gesellschaft für Rheumatologie. Deutsche Gesellschaft für Orthopädische Rheumatologie. Gesellschaft für Kinder- und Jugendrheumatologie. 43. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 29. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 25. wissenschaftliche Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR). Bremen, 02.-05.09.2015. Düsseldorf: German Medical Science GMS Publishing House; 2015. DocER.17

doi: 10.3205/15dgrh071, urn:nbn:de:0183-15dgrh0716

Published: September 1, 2015

© 2015 Jenei-Lanzl et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

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Introduction: In chronic inflammation, prevention of cAMP degradation by phosphodiesterase-4 (PDE4) inhibition can be anti-inflammatory therapy. However, PDE4 inhibition was not effective in rheumatoid arthritis (RA). Recent studies demonstrated that PDE4/β-arrestin interaction at β-adrenoceptors resulted in switching from Gαs to Gαi signaling and ERK1/2 activation. Such a switch might elicit proinflammatory effects 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 Gαi signaling (pertussis toxin), and blockers of protein kinase A (PKA). We measured TNF and investigated co-expression and interaction of PDE4 and β-arrestin by imaging techniques. Expression of pERK1/2 was analyzed by western blotting.

Results: Mixed synoviocytes in RA and OA possessed all major Gαs-coupled neurotransmitter receptors. Under hypoxia, particularly in RA cells, Gαs-coupled receptor agonists unexpectedly increased TNF and respective antagonists decreased TNF. Under hypoxia, rolipram alone or rolipram plus Gαs agonists increased TNF, which was reversed by pertussis toxin or PKA inhibition. In synovial material, PDE4 and β-arrestin were in close apposition as detected by proximity ligation assay. Gαs agonists or rolipram plus Gαs agonists increased pERK1/2 expression.

Conclusion: This study in human arthritic synovial tissue presents an unexpected proinflammatory switch from Gαs to Gαi signaling, which depends on PDE4/β-arrestin interaction. This phenomenon is most probably responsible for reduced efficacy of PDE4 inhibitors and Gαs agonists in RA.