Abstract
Atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor used in the treatment of atherosclerosis and dyslipidemia. Studies have evaluated the utility of statins in the treatment of skin inflammation but with varied results. In the present study, we investigated the effect of atorvastatin on TNF-α release and keratinocyte proliferation in vitro and in acute and chronic 12-O-tetradecanoylphorbol-13-acetate (TPA) induced skin inflammation in vivo. Atorvastatin significantly inhibited lipopolysacharide induced TNF-α release in THP-1 cells and keratinocyte proliferation in HaCaT cells. In an acute study, topical atorvastatin showed dose dependent reduction in TPA induced skin inflammation with highest efficacy observed at 500 µg/ear dose. In chronic study, topical atorvastatin significantly reduced TPA induced ear thickness, ear weight, cutaneous cytokines, MPO activity and improved histopathological features comparable to that of dexamethasone. Atorvastatin also inhibited TPA stimulated NF-κB activation in mouse ear. In conclusion, our results suggest that atorvastatin ameliorates TPA induced skin inflammation in mice at least in part, due to inhibition of cytokine release and NF-κB activation and may be beneficial for the treatment skin inflammation like psoriasis.
Similar content being viewed by others
References
Adami, M., A.D.S. Prudente, D.A.G.B. Mendes, C.D.S. Horinouchi, D.A. Cabrini, and M.F. Ouki. 2012. Simvastatin ointment, a new treatment for skin inflammatory conditions. Journal of Dermatological Science 66: 127–135.
Amigo, M., M. Paya, S. De Rosa, and M.C. Terencio. 2007. Antipsoriatic effects of avarol-3-thiosalicylate are mediated by inhibition of TNF-α generation and NF-kB activation in mouse skin. British Journal of Pharmacology 152: 353–365.
Banno, T., A. Gazel, and M. Blumenberg. 2005. Pathway-specific profiling identifies the NF-kappa B-dependent tumor necrosis factor alpha-regulated genes in epidermal keratinocytes. Journal of Biological Chemistry 280: 18973–18980.
Blanco-Colio, L.M., J. Tunon, J.L. Martin-Ventura, and J. Egido. 2003. Antiinflammatory and immunomodulatory effects of statins. Kidney International 63: 12–23.
Boehncke, W., K. Hardt-Weinelt, H. Nilsson, M. Wolter, M. Dohlsten, F.R. Ochsendorf, R. Kufmann, and P. Antonsson. 2001. Anatagnoistic effects of the staphylococcal enterotoxin a mutant, SEA on psoriasis in SCID-hu xenogeneic transplantation model. Journal of Investigative Dermatology 116: 596–601.
Bracht, L., S.M. Caparroz-Assef, T.F.S. Magon, A.M.V. Ritter, R.K.N. Cuman, and C.A. Bersani-Amado. 2011. Topical anti-inflammatory effect of hypocholesrolemic drugs. Journal of Pharmacy and Pharmacology 63: 971–975.
Bradley, P.P., D.A. Priebat, R.D. Christensen, and G. Rothstein. 1982. Measurement of cutaneous inflammation: Estimation of neutrophil content with an enzyme marker. Journal of Investigative Dermatology 78: 206–209.
Gottlieb, A.B. 2005. Therapeutic options in the treatments of psoriasis and atopic dermatitis. Journal of the American Academy of Dermatology 53: S3–S16.
Johnson-Huang, L.M., N.S. McNutt, J.G. Krueger, and M.A. Lowes. 2009. Cytokine-producing dendritic cells in the pathogenesis of inflammatory skin diseases. Journal of Clinical Immunology 29: 247–256.
Kumar, K.G., R. Damotharan, N.M. Kulkarni, M.Y.A. Mahat, J. Gunasekaran, and M. Ashfaque. 2011. Embelin reduces cutaneous TNF-α level and ameliorate skin edema in acute and chronic model of skin inflammation in mice. European Journal of Pharmacology 662: 63–69.
Kundu, J.K., Y.K. Shin, and Y.J. Surh. 2006. Resveratrol modulates phorbol ester-induced pro-inflammatory signal transduction pathways in mouse skin in vivo: NF-kappaB and AP-1 as prime targets. Biochemical Pharmacology 72: 1506–1515.
Levy, J.H. 1996. The human inflammatory response. Journal of Cardiovascular Pharmacology 27(1): S31–S37.
Li, M., X. Zhong, Z. He, M. Wen, J. Li, X. Peng, G. Liu, et al. 2012. Effect of erythromycin on cigarette-induced histone deacetylase protein expression and nuclear factor-κB activity in human macrophages in vitro. International Immunopharmacology 12(4): 643–650.
Lowes, M.A., A.M. Bowcock, and J.G. Krueger. 2007. Pathogenesis and therapy of psoriasis. Nature 22: 866–873.
Namazi, M.R. 2004. Statins: novel additions to the dermatological arsenal? Experimental Dermatology 13: 337–339.
Ortego, M., C. Bustos, M.A. Harnandez-Presa, J. Tunon, C. Diaz, G. Hernandez, et al. 1999. Atorvastatin reduces NF-kB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells. Atherosclerosis 147: 253–261.
Quivy, V., and C. Van Lint. 2004. Regulation at multiple levels of NF- kappa B-mediated transactivation by protein acetylation. Biochemical Pharmacology 68: 1221–1229.
Stanley, P.L., S. Steiner, M. Havens, and K.M. Tramposch. 1991. Mouse skin inflammation induced by multiple topical applications of 12-O-tetradecanoylphorbol-13-acetate. Skin Pharmacology 4: 262–271.
Wei, W., S. Lin, Y. Chen, C. Wen, C. Huang, A. Palanisamy, et al. 2011. Topical application of marine briarane-type diterpenes effectively inhibits 12-O-tetradecanoylphorbol-13-acetate- induced inflammation and dermatitis in murine skin. Journal of Biomedical Science 18: 94.
Yang, S.S., R. Li, X. Qu, W. Fang, and Z. Quan. 2012. Atorvastatin decreases toll-like receptor 4 expression and downstream signaling in human monocyte leukemia cells. Cellular Immunology 279: 96–102.
Youssef, S., O. Stuve, J.C. Patarroyo, P.J. Ruiz, J.L. Radosevich, E.M. Hur, et al. 2002. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420: 78–84.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kulkarni, N.M., Muley, M.M., Jaji, M.S. et al. Topical atorvastatin ameliorates 12-O-tetradecanoylphorbol-13-acetate induced skin inflammation by reducing cutaneous cytokine levels and NF-κB activation. Arch. Pharm. Res. 38, 1238–1247 (2015). https://doi.org/10.1007/s12272-014-0496-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-014-0496-0