Rheumatology Advance Access originally published online on October 13, 2006
Rheumatology 2007 46(4):579-585; doi:10.1093/rheumatology/kel276
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The differential expression of corticosteroid receptor isoforms in corticosteroid-resistant and -sensitive patients with rheumatoid arthritis
1Bone & Joint Research Unit, Barts and The London, Queen Mary's School of Medicine & Dentistry, University of London, Charterhouse Square, London EC1M 6BQ and 2Department of Rheumatology, Barts & The Royal London and Newham University Hospitals, London, UK.
Correspondence to: I. C. Chikanza, Newham University Hospital, Glen Road, London E13 8SL, UK. E-mail: icchikanza{at}sachicorp.net
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Abstract |
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Objective. A proportion of patients with rheumatoid arthritis (RA) fail to respond adequately to corticosteroid (CS) therapy. Using an in vitro CS sensitivity bioassay, we have subdivided RA patients into steroid-sensitive (SS) and -resistant (SR) subgroups and this correlates with clinical responses to CS therapy. CSs exert their effects via the CS receptor (CR), which exists as two main isoforms, CR
and CRß. CRß can function as a negative inhibitor of CR. We have hypothesized that steroid resistance in RA patients is due in part to a relative over-expression of the CRß.
Methods. Peripheral blood mononuclear cells (PBMCs) were isolated from SS and SR RA patients. CR and CRß mRNA expression was determined by quantitative real time polymerase chain reaction (qRT–PCR). The ratio of CRß/CR mRNA expression was determined. CR and CRß protein expression by PBMCs was analysed by flow cytometry.
Results. qRT–PCR analysis showed a trend towards higher expression of both CRß and basal CRß/CR ratio in SR RA patients. Stimulation of PBMCs in vitro with concanavalin-A induced a significantly higher CRß mRNA expression, and CRß/CR ratio in SR RA patients compared with SS patients, which was not inhibited by hydrocortisone. Flow cytometry showed that the percentage of PBMCs staining for CRß protein was significantly lower in the SS RA group (SS 43.3 ± 14.8% vs SR 88.6 ± 8.6%; P < 0.0010). The mean intensity of fluorescence CRß staining was higher in the SR RA patients (P < 0.001).
Conclusion. We show for the first time that CRß is over-expressed in SR RA patients and that hydrocortisone fails to inhibit concanavalin-A stimulated increase in CRß mRNA in SR RA patients. This mechanism may contribute in part to the CS hyporesponsiveness seen in some RA patients.
KEY WORDS: Rheumatoid arthritis, Inflammation, Corticosteroid resistance, Corticosteroid receptor, Corticosteroids
*Present address: Adnan Menderes University, School of Medicine, Department of Biochemistry, Aydin 09100, Turkey.
Submitted 25 October 2005;
revised version accepted 4 July 2006.
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