The differential expression of corticosteroid receptor isoforms in corticosteroid-resistant and -sensitive patients with rheumatoid arthritis

Abstract

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, CRα and CRβ. CRβ can function as a negative inhibitor of CRα. We have hypothesized that steroid resistance in RA patients is due in part to a relative over-expression of the CRβ. Methods. Peripheral blood mononuclear cells (PBMCs) were isolated from SS and SR RA patients. CRα and CRβ mRNA expression was determined by quantitative real time polymerase chain reaction (qRT-PCR). The ratio of CRβ/CRα mRNA expression was determined. CRα and CRβ protein expression by PBMCs was analysed by flow cytometry. Results. qRT-PCR analysis showed a trend towards higher expression of both CRβ and basal CRβ/CRα ratio in SR RA patients. Stimulation of PBMCs in vitro with concanavalin-A induced a significantly higher CRβ mRNA expression, and CRβ/CRα 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 CRβ 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 CRβ staining was higher in the SR RA patients (P < 0.001). Conclusion. We show for the first time that CRβ is over-expressed in SR RA patients and that hydrocortisone fails to inhibit concanavalin-A stimulated increase in CRβ mRNA in SR RA patients. This mechanism may contribute in part to the CS hyporesponsiveness seen in some RA patients. © 2007 Oxford University Press.