β₂‐Adrenergic and chemokine receptor antagonists delay the onset and reduce the severity of joint injury in rheumatoid arthritis. β₂‐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 β₂‐adrenergic receptor number and K_d were detected. However, RA patients showed a significantly increased cAMP production and inhibition of TNF‐α production by β₂‐adrenergic stimulation, suggesting that reduced GRK activity is associated with increased sensitivity to β₂‐adrenergic activation.—Lombardi, M. S., Kavelaars, A., Schedlowski, M., Bijlsma, J. W. J., Okihara, K. L., Van de Pol, M., Ochsmann, S., Pawlak, C., Schmidt, R. E., Heijnen, C. J. Decreased expression and activity of G‐protein‐coupled receptor kinases in peripheral blood mono‐nuclear cells of patients with rheumatoid arthritis. FASEB J. 13, 715–725 (1999)