title: Proinflammatory receptor switch from Gαs to Gαi signaling by β-arrestin-mediated PDE4 recruitment in mixed RA synovial cells.
abstract: 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/β-arrestin interaction at β-adrenoceptors resulted in switching from Gαs to Gαi signaling and ERK1/2 activation. Such a switch in signaling might elicit proinflammatory effects. We aimed to investigate this possible Gαs to Gαi 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 Gαi signaling (pertussis toxin), and blockers of protein kinase A (PKA). Under normoxic or hypoxic conditions, proinflammatory TNF was the readout-parameter. We 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. Co-localization and interaction of PDE4 and β-arrestin in synovial tissue and cells was demonstrated. Gαs agonists or rolipram plus Gαs agonists increased pERK1/2 expression.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine I, University Hospital Regensburg, Germany. Electronic address: zsuzsa.jenei-lanzl@ukr.de.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Jenei-Lanzl
authors.affiliation: Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine I, University Hospital Regensburg, Germany.
authors.forename: Janika
authors.initials: J
authors.lastname: Zwingenberg
authors.affiliation: Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine I, University Hospital Regensburg, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Lowin
authors.affiliation: Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine I, University Hospital Regensburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Anders
authors.affiliation: Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine I, University Hospital Regensburg, Germany.
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Straub
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019390:Arrestins / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000378:metabolism*; D011941:Receptors, Adrenergic / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D015398:Signal Transduction; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D011941:Receptors, Adrenergic; D011954:Receptors, Dopamine; D018047:Receptors, Purinergic P1; D014409:Tumor Necrosis Factor-alpha; D000071557:beta-Arrestins; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: Chronic arthritis; G protein-coupled receptors; PDE4; Sympathetic neurotransmitters; TNF; β-arrestin