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Research Communications |
a Department of Immunology, University Hospital for Children and Youth, `Het Wilhelmina Kinderziekenhuis', 3584 EA Utrecht, The Netherlands;
b Institut für Medizinische Psychologie, 45122 Essen, Germany;
c Department of Rheumatology and Clinical Immunology, University Hospital, 3584 CX Utrecht, The Netherlands; and
d Department of Clinical Immunology and
e Department of Medical Psychology, Hannover Medical School, 36025-Hannover, Germany
ß2-Adrenergic and chemokine receptor antagonists delay the
onset and reduce the severity of joint injury in rheumatoid arthritis.
ß2-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
ß2-adrenergic receptor number and
Kd were detected. However, RA patients showed a
significantly increased cAMP production and inhibition of TNF-
production by ß2-adrenergic stimulation, suggesting that
reduced GRK activity is associated with increased sensitivity to
ß2-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 mononuclear cells of patients with rheumatoid
arthritis.
Key Words: immune system • lymphocytes • cytokines • autoimmunity
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