Statins accelerate the onset of collagen type II-induced arthritis in mice
1 Laboratory for Health Protection Research, National Institute for Public Health and the Environment, Antonie van Leeuwenhoeklaan 9, PO Box 1, 3720 BA Bilthoven, the Netherlands
2 Department of Toxicogenomics, Maastricht University, Universiteitssingel 50, PO Box 616, 6200 MD Maastricht, the Netherlands
3 Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, PO Box 80 082, 3508 TB Utrecht, the Netherlands
4 Department of Internal Medicine, Division of Clinical and Experimental Immunology, University Hospital Maastricht, Universiteitssingel 50, PO Box 616, 6200 MD Maastricht, the Netherlands
5 Centre for Substances and Integrated Risk Assessment, National Institute for Public Health and the Environment, Antonie van Leeuwenhoeklaan 9, PO Box 1, 3720 BA Bilthoven, the Netherlands
6 Section on Pharmacology, Toxicology and Biotechnology (FTBB), Medicines Evaluation Board, Graadt van Roggenweg 500, PO Box 8275, 3503 RG Utrecht, the Netherlands
Citation and License
Arthritis Research & Therapy 2012, 14:R90 doi:10.1186/ar3814
See related letter by Mathieu et al., http://arthritis-research.com/content/15/2/402 and response by Vandebriel et al., http://arthritis-research.com/content/15/2/403Published: 26 April 2012
Statins (hydroxymethylglutaryl coenzyme A reductase inhibitors) are effective in reducing the risk of cardiovascular morbidity and mortality in patients with hyperlipidemia, hypertension, or type II diabetes. Next to their cholesterol-lowering activity, statins have immunomodulatory properties. Based on these properties, we hypothesized that statin use may eventually lead to dysregulation of immune responses, possibly resulting in autoimmunity. We have recently shown in an observational study that statin use was associated with an increased risk of developing rheumatoid arthritis. Our objective was to investigate whether a causal relationship could be established for this finding.
The mouse collagen type II (CII)-induced arthritis (CIA) model was used, with immunization, challenge, and euthanasia at days 0, 21, and 42, respectively. Statins were given orally before (day -28 until day 21) or after (day 21 until day 42) CIA induction. Atorvastatin (0.2 mg/day) or pravastatin (0.8 mg/day) was administered. Arthritis was recorded three times a week. Serum anti-CII autoantibodies and cytokines in supernatants from Concanavalin-A-stimulated lymph node cells and CII-stimulated spleen cells were measured.
Statin administration accelerated arthritis onset and resulted in 100% arthritic animals, whereas only seven out of 12 nonstatin control animals developed arthritis. Atorvastatin administration after CIA induction resulted in earlier onset than atorvastatin administration before induction, or than pravastatin administration before or after induction. The arthritic score of animals given pravastatin before CIA induction was similar to that of the nonstatin controls, whereas the other groups that received statins showed higher arthritic scores. Atorvastatin administration, especially before CIA induction, increased anti-CII autoantibody production. IL-2 and IL-17 production by lymph node and spleen cells was higher in CIA animals than in PBS controls, but was not affected by statin administration. While IFNγ production was not affected by CIA induction, atorvastatin administration before CIA induction increased the production of this cytokine.
These data support previous results from our observational studies, indicating a role for statins in the induction of autoimmunity.