Decreased expression and activity of G-protein-coupled receptor kinases in peripheral blood mononuclear cells of patients with rheumatoid arthritis.
Beta2-Adrenergic and chemokine receptor antagonists delay the onset and reduce the severity of joint injury in rheumatoid arthritis. beta2-Adrenergic and chemokine receptors belong to the G-protein-coupled receptor family whose responsiveness is turned off by the G-protein-coupled receptor kinase family (GRK-1 to 6). GRKs phosphorylate receptors in an agonist-dependent manner resulting in receptor/G-protein uncoupling via subsequent binding of arrestin proteins. We assessed the activity of GRKs in lymphocytes of rheumatoid arthritis (RA) patients by rhodopsin phosphorylation. We found a significant decrease in GRK activity in RA subjects that is mirrored by a decrease in GRK-2 protein expression. Moreover, GRK-6 protein expression is reduced in RA patients whereas GRK-5 protein levels were unchanged. In search of an underlying mechanism, we demonstrated that proinflammatory cytokines induce a decrease in GRK-2 protein levels in leukocytes from healthy donors. Since proinflammatory cytokines are abundantly expressed in RA, it may provide an explanation for the decrease in GRK-2 expression and activity in patients. No changes in beta2-adrenergic receptor number and Kd were detected. However, RA patients showed a significantly increased cAMP production and inhibition of TNF-alpha production by beta2-adrenergic stimulation, suggesting that reduced GRK activity is associated with increased sensitivity to beta2-adrenergic activation.
Lombardi
M S
MS
Department of Immunology, University Hospital for Children and Youth, 'Het Wilhelmina Kinderziekenhuis', 3584 EA Utrecht, The Netherlands. s.lombardi@wkz.azu.nl
Kavelaars
A
A
Schedlowski
M
M
Bijlsma
J W
JW
Okihara
K L
KL
Van de Pol
M
M
Ochsmann
S
S
Pawlak
C
C
Schmidt
R E
RE
Heijnen
C J
CJ
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D000368:Aged; D019390:Arrestins / Q000096:biosynthesis; D001172:Arthritis, Rheumatoid / Q000201:enzymology*; D000242:Cyclic AMP / Q000032:analysis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D054774:G-Protein-Coupled Receptor Kinase 5; D054768:G-Protein-Coupled Receptor Kinases; D019204:GTP-Binding Proteins; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000201:enzymology*; D011494:Protein Kinases / Q000096:biosynthesis*; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D015398:Signal Transduction; D013726:Terbutaline / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D051552:beta-Adrenergic Receptor Kinases; D000071557:beta-Arrestins
D000318:Adrenergic beta-Agonists; D019390:Arrestins; D018836:Inflammation Mediators; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D014409:Tumor Necrosis Factor-alpha; D000071557:beta-Arrestins; D000242:Cyclic AMP; D011494:Protein Kinases; D020794:Receptor Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D054774:G-Protein-Coupled Receptor Kinase 5; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6; C517898:GRK5 protein, human; D019204:GTP-Binding Proteins; D013726:Terbutaline