ARTHRITIS & RHEUMATOLOGY Vol. 66, No. 10, October 2014, pp 2685–2693 DOI 10.1002/art.38746 © 2014, American College of Rheumatology Increased Expression of Dopamine Receptors in Synovial Fibroblasts From Patients With Rheumatoid Arthritis Inhibitory Effects of Dopamine on Interleukin-8 and Interleukin-6 Silvia Capellino, 1 Marco Cosentino, 2 Alessandra Luini, 2 Raffaella Bombelli, 2 Torsten Lowin, 1 Maurizio Cutolo, 3 Franca Marino, 2 and Rainer H. Straub 1 Objective. Observations in both animal models of arthritis and patients with rheumatoid arthritis (RA) suggest a role for dopamine and its receptors in RA. Because synovial fibroblasts (SFs) contribute to inflam- mation and joint destruction in RA, the aim of this study was to investigate dopaminergic pathways in SFs ob- tained from patients with RA and, for comparison, in SFs from patients with osteoarthritis (OA) undergoing knee joint replacement surgery. Methods. The expression of all dopamine recep- tors (D 1 –D 5 ) and dopamine transporter was assessed by immunofluorescence and immunohistochemical stain- ing. The levels of dopamine receptor and tyrosine hydroxylase messenger RNA were measured by real- time polymerase chain reaction. The intracellular content of dopamine, its precursor, and its main metab- olites was assayed by high-performance liquid chroma- tography. The influence of dopamine on proinflam- matory interleukin-6 (IL-6) and IL-8, matrix metalloproteinase 3, and tissue inhibitor of metallopro- teinases 1 (TIMP-1) and TIMP-2 was studied in SFs. Results. SFs possess an intrinsic dopaminergic system, including dopamine receptors, dopamine trans- porter, and tyrosine hydroxylase, and contain dopa- mine, its precursor, and its main metabolites. SFs from patients with RA, in comparison with those from pa- tients with OA, showed increased expression of dopa- mine receptors D 1 and D 5 , and exogenous dopamine strongly inhibited the production of IL-8 in patients with RA. Conclusion. SFs from patients with RA and pa- tients with OA show a dopaminergic phenotype. The expression of D1-like dopamine receptors was higher in RASFs, and this increased expression may lead to antiinflammatory effects, as demonstrated by the ex- pression of IL-8. Studies in animal models and patients with RA are needed to assess the therapeutic potential of endogenous, local production of dopamine in syno- viocytes. Dopamine belongs, together with noradrenaline and adrenaline, to the catecholamine family, and it is an established neurotransmitter in the central nervous sys- tem controlling movement, emotion, cognition, and neu- roendocrine functions (1). Recent evidence, however, increasingly supports a key role of dopaminergic path- ways in the modulation of immunity (2–5). Dopamine acts on 5 different dopamine receptors belonging to the 7-transmembrane, G protein–coupled receptor family, which are grouped into 2 families: the D1-like dopamine Supported by the German Research Society (DFG FOR696, CA 933/1-1 and LO-1686/1-1). 1 Silvia Capellino, PhD (current address: Johns Hopkins Uni- versity School of Medicine, Baltimore, Maryland), Torsten Lowin, PhD, Rainer H. Straub, MD: University Hospital Regensburg, Re- gensburg, Germany; 2 Marco Cosentino, MD, PhD, Alessandra Luini, BSc, Raffaella Bombelli, PharmD, Franca Marino, PhD: University of Insubria, Varese, Italy; 3 Maurizio Cutolo, MD: University of Genoa, Genoa, Italy. Drs. Capellino and Cosentino contributed equally to this work. Dr. Cutolo has received consulting fees, speaking fees, and/or honoraria from Actelion, Bristol-Myers Squibb, Mundipharma, AbbVie, Horizon, and Celltrion (more than $10,000 each). Address correspondence to Silvia Capellino, PhD, Johns Hopkins University School of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, 600 North Wolfe Street, Balti- more, MD 21287. E-mail: silvia_capellino@yahoo.it. Submitted for publication October 24, 2013; accepted in revised form June 10, 2014. 2685