Anti-inflammatory effects of atorvastatin on peripheral blood mononuclear cells and synovial fibroblasts in rheumatoid arthritis.
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 microM 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 (Th1) 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 (Th1) and a local effect on FLS. These findings may provide a scientific rationale for statins as add-on therapy in RA.
Blaschke
S
S
Department of Nephrology and Rheumatology, University of Goettingen, Germany. sblasch@gwdg.de
Viereck
V
V
Schwarz
G
G
Klinger
H M
HM
Guerluek
S
S
Müller
G A
GA
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy / Q000276:immunology; D000069059:Atorvastatin; D015415:Biomarkers / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects*; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000276:immunology / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D011336:Probability; D011758:Pyrroles / Q000494:pharmacology*; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000166:cytology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism; D055815:Young Adult; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000069059:Atorvastatin; D015415:Biomarkers; D016827:CD8 Antigens; D006684:HLA-DR Antigens; D006538:Heptanoic Acids; D015850:Interleukin-6; D037181:Lectins, C-Type; D011758:Pyrroles; D000099192:CD69 Antigens