Abstract
Although statins have been successfully administered in the treatment of hypercholesterolemia and cardiovascular disease due to their lipid-lowering and anti-atherosclerotic action, they have shown immunomodulatory effects in several studies with immune-mediated diseases. The aim of this study was to investigate the effects of statins treatment on Th1, Th2, and Th17 cytokines production from stimulated peripheral blood mononuclear cells (PBMCs) obtained from Systemic Sclerosis (SSc) patients. We recruited 21 patients classified according to the American College of Rheumatology criteria for SSc for PBMCs culture analysis. Cytokine levels (IL-2, IL-4, IL-6, IL-10, TNF, IFN-γ, IL-17A, and IL-17F) were quantified by ELISA or CBA, and patients were assessed for clinical and exam’s variables. Simvastatin and atorvastatin at 50 μM promoted reduction in all cytokine levels with statistical significance, except for IL-6, which had its reduction only induced by the use of simvastatin. Statins, particularly simvastatin, appear to have an immunosuppressive effect in reducing all cytokine secretion levels from PBMCs of SSc in a dose-dependent manner.
This is a preview of subscription content, log in via an institution to check access.
References
Baraut, J., L. Michel, F. Verrecchia, and D. Farge. 2010. Relationship between cytokine profiles and clinical outcomes in patients with systemic sclerosis. Autoimmunity Reviews. 10 (2): 65–73. https://doi.org/10.1016/j.autrev.2010.08.003.
Chizzolini, C., N.C. Brembilla, E. Montanari, and M.E. Truchetet. 2011. Fibrosis and immune dysregulation in systemic sclerosis. Autoimmunity Reviews. 10 (5): 276–281. https://doi.org/10.1016/j.autrev.2010.09.016.
Trifari, S., C.D. Kaplan, E.H. Tran, N.K. Crellin, and H. Spits. 2009. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nature Immunology 10 (8): 864–871. https://doi.org/10.1038/ni.1770.
Hwang SY, Kim JY, Kim KW, Park MK, Moon Y, Kim WU et al. IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kappaB- and PI3-kinase/Akt-dependent pathways. Arthritis Research & Therapy. 2004;6(2):R120–R128. doi:https://doi.org/10.1186/ar1038.
Murata, M., M. Fujimoto, T. Matsushita, Y. Hamaguchi, M. Hasegawa, K. Takehara, K. Komura, and S. Sato. 2008. Clinical association of serum interleukin-17 levels in systemic sclerosis: is systemic sclerosis a Th17 disease? Journal of Dermatological Science. 50 (3): 240–242. https://doi.org/10.1016/j.jdermsci.2008.01.001.
Rossi, M., L. Bazzichi, L. Ghiadoni, I. Mencaroni, F. Franzoni, and S. Bombardieri. 2012. Increased finger skin vasoreactivity and stimulated vasomotion associated with simvastatin therapy in systemic sclerosis hypercholesterolemic patients. Rheumatology International 32 (12): 3715–3721. https://doi.org/10.1007/s00296-011-2183-5.
Kim, S.I., D.C. Han, and H.B. Lee. 2000. Lovastatin inhibits transforming growth factor-beta1 expression in diabetic rat glomeruli and cultured rat mesangial cells. Journal of the American Society of Nephrology : JASN. 11 (1): 80–87.
Goppelt-Struebe, M., A. Hahn, D. Iwanciw, M. Rehm, and B. Banas. 2001. Regulation of connective tissue growth factor (ccn2; ctgf) gene expression in human mesangial cells: modulation by HMG CoA reductase inhibitors (statins). Molecular Pathology : MP. 54 (3): 176–179.
Forero-Pena, D.A., and F.R. Gutierrez. 2013. Statins as modulators of regulatory T-cell biology. Mediators of Inflammation 2013: 167086–167010. https://doi.org/10.1155/2013/167086.
Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis and Rheumatism 1980;23(5):581–590.
Dantas, A.T., A.R. de Almeida, M. Sampaio, M.F. Cordeiro, L.F. da Rocha Jr., P.S.S. de Oliveira, et al. 2017. Corticosteroid inhibits chemokines production in systemic sclerosis patients. Steroids 127: 24–30. https://doi.org/10.1016/j.steroids.2017.08.012.
Pereira, M.C., P.R. Cardoso, L.F. Da Rocha Jr., M.J. Rego, S.M. Goncalves, F.A. Santos, et al. 2014. Simvastatin inhibits cytokines in a dose response in patients with rheumatoid arthritis. Inflammation Research 63 (4): 309–315. https://doi.org/10.1007/s00011-013-0702-4.
Bessler, H., H. Salman, M. Bergman, R. Straussberg, and M. Djaldetti. 2005. In vitro effect of statins on cytokine production and mitogen response of human peripheral blood mononuclear cells. Clinical Immunology 117 (1): 73–77. https://doi.org/10.1016/j.clim.2005.06.014.
Cherfan, P., A. Tompa, A. Wikby, S. Lofgren, and L. Jonasson. 2007. Effects of simvastatin on human T cells in vivo. Atherosclerosis 193 (1): 186–192. https://doi.org/10.1016/j.atherosclerosis.2006.06.022.
Blaschke, S., V. Viereck, G. Schwarz, H.M. Klinger, S. Guerluek, and G.A. Muller. 2009. Anti-inflammatory effects of atorvastatin on peripheral blood mononuclear cells and synovial fibroblasts in rheumatoid arthritis. Scandinavian Journal of Rheumatology. 38 (4): 235–239. https://doi.org/10.1080/03009740802572475.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflicts of interest.
The study protocol was approved by the ethics committee of Universidade Federal de Pernambuco (CAAE: 63515916.1.0000.5208), according to the principles of the Declaration of Helsinki, and informed consent was obtained from all subjects.
Additional information
The original version of this article was revised: One of the author’s surname was incorrect. Anderson Ferreira de Almeida should be captured as Anderson Rodrigues de Almeida.
Rights and permissions
About this article
Cite this article
Gonçalves, R.S.G., Dantas, A.T., Pereira, M.C. et al. Statins Inhibit Cytokines in a Dose-Dependent Response in Patients with Systemic Sclerosis. Inflammation 42, 407–411 (2019). https://doi.org/10.1007/s10753-018-0907-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10753-018-0907-3