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Randomized Controlled Trial
. 2011 May;52(5):1023-32.
doi: 10.1194/jlr.M010876. Epub 2011 Mar 2.

Atorvastatin upregulates regulatory T cells and reduces clinical disease activity in patients with rheumatoid arthritis

Ting-Ting Tang  1 , You Song, Ying-Jun Ding, Yu-Hua Liao, Xian Yu, Rong Du, Hong Xiao, Jing Yuan, Zi-Hua Zhou, Meng-Yang Liao, Rui Yao, Harish Jevallee, Guo-Ping Shi, Xiang Cheng
Affiliations
Randomized Controlled Trial

Atorvastatin upregulates regulatory T cells and reduces clinical disease activity in patients with rheumatoid arthritis

Ting-Ting Tang et al. J Lipid Res. 2011 May.

Abstract

In this study, we investigated the hypothesis that regulatory T cells (T(reg)) are involved in the immunomodulatory effects of statins on rheumatoid arthritis (RA) patients. The 12-week study cohort consisted of 55 RA patients and 42 control subjects allocated to either a group treated with atorvastatin (AT) (20 mg/day) or a non-AT group. T(reg) numbers, suppressive function, serum inflammatory markers, and disease activity were evaluated before and after the therapy. Furthermore, the effects of AT on the frequency and suppressive function of T(reg) were determined in vitro. Our data revealed that the suppressive function of T(reg) from RA patients significantly decreased compared with that of control subjects. AT significantly reduced erythrosedimentation, C-reactive protein, and disease activity. Concomitantly, T(reg) numbers and suppressive functions were significantly improved by AT. Consistent with the in vivo experiments, AT promoted the generation of T(reg) from primary T cells and enhanced preexisting T(reg) function in vitro. Moreover, we showed that PI3K-Akt-mTOR and ERK signal pathways were involved in the induction of T(reg) by AT. In conclusion, AT significantly increased T(reg) numbers and restored their suppressive function in the RA patients, and this may be relevant in the modulation of uncontrolled inflammation in this disorder.

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Figures

Fig. 1.
Fig. 1.
Determination of Treg in RA patients and control subjects is shown. (A) PBMCs from 55 RA patients and 42 control subjects were stained for CD4, CD25, and Foxp3 and analyzed by flow cytometry. Dot plots are representative fluorescence-activated cell sorting pictures from an RA patient. (B) Histograms represent data from a RA patient when the gated Treg were further phenotypically analyzed for the indicated markers (black line, isotype control; blue line, control subject; red line, RA patient). (C) Collective analyses of Treg percentages in the two groups are shown. (D) Expression of Foxp3 mRNA in PBMCs was compared between the two groups by using real-time PCR.
Fig. 2.
Fig. 2.
Compromised Treg suppressive function in RA patients is shown. (A) Magnetic-sorted CD4+ CD25+CD127low Treg and CD4+CD25− Tresp from RA patients and control subjects were mixed at the indicated ratios and tested in the proliferation assay. (B) Comparison of cytokines production by activated CD4+CD25− T cells from the RA patients or the control subjects is shown. (C) Comparison of cytokines production by CD4+CD25− T cells from RA patients when cells were cocultured with autologous Treg or Treg from control subjects is shown. *, p < 0.05, or **, p < 0.01 versus control subjects.
Fig. 3.
Fig. 3.
Influence of AT on circulating Treg in vivo is shown. (A) Dot plots show representative fluorescence-activated cell sorting pictures of CD4+ CD25+ Foxp3+ Treg from a single person in four groups. (B) The frequency of Treg was compared among four groups before (RA-AB, RA-CB, Con-AB, and Con-CB) and after 12 weeks (RA-A1, RA-C1, Con-A1, and Con-C1) of treatment. (C) The proliferation of Tresp when they were cultured alone or together with Treg at a 2:1 ratio were compared among four groups before and after 12 weeks of treatment. *, p < 0.05 versus the indicated group.
Fig. 4.
Fig. 4.
Effects of AT on Treg in vitro are shown. (A) AT induced CD4+CD25+Foxp3+ from primary CD4+CD25− T cells in a dose-dependent manner and l-mevalonate reversed the induction of these cells by AT. (B) CD4+CD25+Foxp3+ induced only in the presence of AT suppressed the proliferation of Tresp. (C.) Treg incubated with AT for 24 h showed an increased expression of Foxp3. (D.) Treg preincubated with AT showed enhanced suppressive function. The data are representative of three independent experiments with different donors. *, p < 0.05, and **, p < 0.01 versus medium; #, p < 0.05 versus a 1:0 Tresp/Treg ratio.
Fig. 5.
Fig. 5.
AT induced the generation of Treg accompanied by the inhibition of PI3K-Akt-mTOR and ERK signal transduction pathways. (A, upper panel) Representative Western blots show the indicated protein in primary CD4+CD25− T cells treated with AT; (lower panel) mean densitometric analyses of the relative phosphorylated protein to total protein are shown. (B left) Representative fluorescence-activated cell sorting (FACS) results are shown in primary CD4+CD25− T cells treated with AT (10 μM), the ERK inhibitor (U0126, 5 μM), or the PI3K-Akt inhibitor (LY294002, 5 μM); (right,) collective analyses of Treg induced by AT, U0126 or LY294002, are shown. The data are representative of three or four independent experiments with different donors. *, p < 0.05, and **, p < 0.01 versus medium.
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