Anti-inflammatory effects of atorvastatin on peripheral blood mononuclear cells and synovial fibroblasts in rheumatoid arthritis

摘要

Objective: Statins, such as atorvastatin (ATV), are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors known to exert lipid-lowering but also anti-inflammatory, effects. In this study, we analysed the in vitro effects of ATV on peripheral blood mononuclear cells (PBMCs) and fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA), a chronic inflammatory joint disease.Methods: PBMCs isolated from 25 RA patients and 20 healthy blood donors were stimulated in vitro with 0.1 muM ATV for 24 h. PBMC cultures were analysed for cell surface markers to characterize T-cell subtypes (CD4, CD8, CD69, HLA-DR) by flow cytometry and for T helper cell type 1 (Thl) and type 2 (Th2) cytokines [interferon-gamma (IFN-gamma), interleukin-4 (IL-4), IL-10] in culture supernatants by enzyme-linked immunosorbent assay (ELISA). Furthermore, RNA isolated from ATV-stimulated RA-FLS pre- and post-ATV stimulation was analysed by microarray and quantitative reverse transcription polymerase chain reaction (RT-PCR). Results: Flow cytometric analysis of T-cell subsets revealed no significant differences for CD4, CD8, CD69, and HLA-DR surface marker expression of PBMCs in RA patients and healthy controls after ATV stimulation. However, the proportion of IFN-gamma expressing CD4~+ T cells and the IFN-gamma cytokine concentrations in culture supernatants were significantly reduced in T-cell cultures from RA patients. In ATV-stimulated FLS a significant downregulation of proinflammatory cytokine (IL-6) and chemokine (IL-8) expression was detected (p< 0.001).Conclusions: Our study demonstrates a marked in vitro anti-inflammatory activity of ATV in RA including a systemic effect on a pathogenic CD4~+ T-cell population (Thl) and a local effect on FLS. These findings may provide a scientific rationale for statins as add-on therapy in RA.