Decreased expression and activity of G-protein-coupled receptor kinases in peripheral blood mononuclear cells of patients with rheumatoid arthritis

beta(2)-Adrenergic and chemokine receptor antagonists delay the onset and reduce the severity of joint injury in rheumatoid arthritis. beta(2)-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 beta(2)-adrenergic receptor number and K-d were detected. However, RA patients showed a sig nificantly increased cAMP production and inhibition of TNF-alpha production by beta(2)-adrenergic stimulation, suggesting that reduced GRK activity is associated with increased sensitivity to beta(2)-adrenergic activation.