The immune suppressive effect of dexamethasone in rheumatoid arthritis is accompanied by upregulation of interleukin 10 and by differential changes in interferon gamma and interleukin 4 production

Abstract

Objectives: The influence of dexamethasone on interleukin 10 (IL10) production and the type 1 (T1)/type 2 (T2) T cell balance found in rheumatoid arthritis (RA) was studied.

Methods: Peripheral blood mononuclear cells (PB MNC) were isolated from 14 RA patients both before and 7 and 42 days after high dose dexamethasone pulse therapy. The ex vivo production of IL10, interferon gamma (IFN gamma) (T1 cell), and IL4 (T2 cell) by PB MNCs was assessed, along with parameters of disease activity (erythrocyte sedimentation rate, C reactive protein, Visual Analogue Scale, Thompson joint score). In addition, the in vitro effect of dexamethasone (0.02, 0.2, and 2 microM) on PB MNC IL10, IFN gamma, and IL4 production was studied.

Results: Dexamethasone pulse therapy resulted in a rapid and sustained decrease in RA disease activity. IL10 production increased after dexamethasone treatment and this was sustained for at least six weeks. A transient strong decrease in IFN gamma was seen shortly after corticosteroid treatment, while IL4 only decreased slightly. This led to an increased IL-4/IFN gamma ratio. In vitro, IL10 production was not detectable, IFN gamma and IL4 decreased, but the effect was more pronounced for IFN gamma than for IL4, which again resulted in an increased IL4/IFN gamma ratio.

Conclusion: Dexamethasone therapy in RA patients leads to a rapid, clinically beneficial effect. The upregulation of IL10 production may be involved in the prolonged clinical benefit. The strong immunosuppressive effect is most evident in the decrease in IFN gamma, and is therefore accompanied by a relative shift towards T2 cell activity. In vitro evaluation showed that this shift in T cell balance was a direct effect of dexamethasone and thus independent of the hypothalamic-pituitary-adrenal axis.

Figure 1

(A) RA disease activity; mean (SEM) values of Thompson joint score, erythrocyte sedimentation rate, C reactive protein, and Visual Analogue Scale of 14 RA patients with active disease are given. Patients received 200 mg dexamethasone iv at day 1, 3, and 5. Asterisks indicate a statistical significant difference on day 7 and day 42. (B) Ex vivo IFNγ and IL4 production, as measures for T1 and T2 T cell activity respectively, of PB MNC of 14 RA patients who received 200 mg dexamethasone iv at day 1, 3, and 5. Mean (SEM) values are given. IFNγ and IL4 are shown on the left axis and the average of the individual IL4/IFNγ ratios on the right axis. Asterisks indicate a statistical significant difference on day 7. (C) Ex vivo measured IL10 production of PB MNC of 10 RA patients who received 200 mg dexamethasone iv at day 1, 3, and 5. Mean (SEM) values are given. Asterisk indicates a statistical significant difference on day 42.

Figure 2

(A) In vitro IFNγ and IL4 production, as measures for T1 and T2 T cell activity respectively, of PB MNC obtained from 14 RA patients before dexamethasone pulse therapy, which in vitro have been exposed to dexamethasone. Mean (SEM) values are given. IFNγ and IL4 are shown on the left axis and the average of the individual IL4/IFNγ ratios on the right axis. Asterisks indicate a statistical significant difference at all different dexamethasone concentrations. (B) In vitro IFNγ and IL4 production, as measure for T1 and T2 T cell activity respectively, of PB MNC of seven randomly selected RA patients, in vitro exposed to dexamethasone. Mean (SEM) values are given. IFNγ and IL4 are shown on the left axis and the average of the individual IL4/IFNγ ratios on the right axis. Asterisks indicate a statistical significant difference at all dexamethasone concentrations.