Advertisement

Statins Inhibit Monocyte Chemotactic Protein 1 Expression in Endometriosis

Abstract

Statins are potent inhibitors of the endogenous mevalonate pathway. Besides inhibiting cholesterol biosynthesis, statins may also demonstrate anti-inflammatory properties. Inflammation is implicated in the attachment and invasion of endometrial cells to the peritoneal surface and growth of ectopic endometrium by inducing proliferation and angiogenesis. In this study, the effect of statins on monocyte chemotactic protein 1 (MCP-1) expression in endometriotic implants in nude mouse model and in cultured endometriotic cells was evaluated. In mouse model, simvastatin decreased MCP-1 expression in a dose-dependent manner in endometriotic implants (P < .05). Similarly, both simvastatin and mevastatin revealed a dose-dependent inhibition of MCP-1 production in cultured endometriotic cells (P < .01). This inhibitory effect of the statins on MCP-1 production was reversed by the downstream substrates of the mevalonate pathway. Moreover, statins decreased MCP-1 messenger RNA expression in cultured endometriotic cells (P < .05). In conclusion, statins exert anti-inflammatory effect in endometriotic cells and could provide a potential treatment of endometriosis in the future.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 510

This is the net price. Taxes to be calculated in checkout.

References

  1. 1.

    Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;343(6257): 425–430.

  2. 2.

    Takai Y, Sasaki T, Matozaki T. Small GTP-binding proteins. Physiol Rev. 2001;81(1): 153–208.

  3. 3.

    Van Aelst L, D’Souza-Schorey C. Rho GTPases and signaling networks. Genes Dev. 1997;11(18): 2295–2322.

  4. 4.

    Chow SC. Immunomodulation by statins: mechanisms and potential impact on autoimmune diseases. Arch Immunol Ther Exp (Warsz). 2009;57(4): 243–251.

  5. 5.

    Kuipers HF, van den Elsen PJ. Immunomodulation by statins: inhibition of cholesterol vs. isoprenoid biosynthesis. Biomed Pharmacother. 2007;61(7): 400–407.

  6. 6.

    Aktas O, Waiczies S, Smorodchenko A, et al. Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin. J Exp Med. 2003;197(6): 725–733.

  7. 7.

    Okamoto H, Koizumi K, Kamitsuji S, et al. Beneficial action of statins in patients with rheumatoid arthritis in a large observational cohort. J Rheumatol. 2007;34(5): 964–968.

  8. 8.

    Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004;363(9421): 1607–1608.

  9. 9.

    McCarey DW, McInnes IB, Madhok R, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004;363(9426): 2015–2021.

  10. 10.

    Bruner-Tran KL, Osteen KG, Duleba AJ. Simvastatin protects against the development of endometriosis in a nude mouse model. J Clin Endocrinol Metab. 2009;94(7): 2489–2494.

  11. 11.

    Cakmak H, Guzeloglu-Kayisli O, Kayisli UA, Arici A. Immune-endocrine interactions in endometriosis. Front Biosci (Elite Ed). 2009;1: 429–443.

  12. 12.

    Arici A, Oral E, Attar E, Tazuke SI, Olive DL. Monocyte chemotactic protein-1 concentration in peritoneal fluid of women with endometriosis and its modulation of expression in mesothelial cells. Fertil Steril. 1997;67(6): 1065–1072.

  13. 13.

    Ulukus M, Ulukus EC, Tavmergen Goker EN, Tavmergen E, Zheng W, Arici A. Expression of interleukin-8 and monocyte chemotactic protein 1 in women with endometriosis. Fertil Steril. 2009;91(3): 687–693.

  14. 14.

    Garcia-Velasco JA, Seli E, Arici A. Regulation of monocyte chemotactic protein-1 expression in human endometrial stromal cells by integrin-dependent cell adhesion. Biol Reprod. 1999;61(2): 548–552.

  15. 15.

    Kayisli UA, Mahutte NG, Arici A. Uterine chemokines in reproductive physiology and pathology. Am J Reprod Immunol. 2002;47(4): 213–221.

  16. 16.

    Lin J, Gu Y. Effect of monocyte chemoattractant protein-1 and estradiol on the secretion of vascular endothelial growth factor in endometrial stromal cells in vitro. Fertil Steril. 2005;84(6): 1793–1796.

  17. 17.

    Bruner-Tran KL, Zhang Z, Eisenberg E, Winneker RC, Osteen KG. Down-regulation of endometrial matrix metalloproteinase-3 and -7 expression in vitro and therapeutic regression of experimental endometriosis in vivo by a novel nonsteroidal progesterone receptor agonist, tanaproget. J Clin Endocrinol Metab. 2006;91(4): 1554–1560.

  18. 18.

    Arici A, Head JR, MacDonald PC, Casey ML. Regulation of interleukin-8 gene expression in human endometrial cells in culture. Mol Cell Endocrinol. 1993;94(2): 195–204.

  19. 19.

    Kayisli UA, Selam B, Guzeloglu-Kayisli O, Demir R, Arici A. Human chorionic gonadotropin contributes to maternal immuno-tolerance and endometrial apoptosis by regulating Fas-Fas ligand system. J Immunol. 2003;171(5): 2305–2313.

  20. 20.

    Sampson JA. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obst Gynecol. 1927;14: 442–469.

  21. 21.

    Ulukus M, Cakmak H, Arici A. The role of endometrium in endometriosis. J Soc Gynecol Investig. 2006;13(7): 467–476.

  22. 22.

    Oktem M, Esinler I, Eroglu D, Haberal N, Bayraktar N, Zeyneloglu HB. High-dose atorvastatin causes regression of endometriotic implants: a rat model. Hum Reprod. 2007;22(5): 1474–1480.

  23. 23.

    Esfandiari N, Khazaei M, Ai J, et al. Effect of a statin on an in vitro model of endometriosis. Fertil Steril. 2007;87(2): 257–262.

  24. 24.

    Nasu K, Yuge A, Tsuno A, Narahara H. Simvastatin inhibits the proliferation and the contractility of human endometriotic stromal cells: a promising agent for the treatment of endometriosis. Fertil Steril. 2009;92(6): 2097–2099.

  25. 25.

    Piotrowski PC, Kwintkiewicz J, Rzepczynska IJ, et al. Statins inhibit growth of human endometrial stromal cells independently of cholesterol availability. Biol Reprod. 2006;75(1): 107–111.

  26. 26.

    Sokalska A, Wong DH, Cress A, et al. Simvastatin induces apoptosis and alters cytoskeleton in endometrial stromal cells. J Clin Endocrinol Metab. 2010;95(7): 3453–3459.

  27. 27.

    Dmowski WP, Ding J, Shen J, Rana N, Fernandez BB, Braun DP. Apoptosis in endometrial glandular and stromal cells in women with and without endometriosis. Hum Reprod. 2001;16(9): 1802–1808.

  28. 28.

    Murk W, Atabekoglu CS, Cakmak H, et al. Extracellularly signal-regulated kinase activity in the human endometrium: possible roles in the pathogenesis of endometriosis. J Clin Endocrinol Metab. 2008;93(9): 3532–3540.

  29. 29.

    Zhou HE, Nothnick WB. The relevancy of the matrix metalloproteinase system to the pathophysiology of endometriosis. Front Biosci. 2005;10: 569–575.

  30. 30.

    Furman C, Copin C, Kandoussi M, et al. Rosuvastatin reduces MMP-7 secretion by human monocyte-derived macrophages: potential relevance to atherosclerotic plaque stability. Atherosclerosis. 2004;174(1): 93–98.

  31. 31.

    Lazzerini PE, Capecchi PL, Nerucci F, et al. Simvastatin reduces MMP-3 level in interleukin 1beta stimulated human chondrocyte culture. Ann Rheum Dis. 2004;63(7): 867–869.

  32. 32.

    Wilson WR, Evans J, Bell PR, Thompson MM. HMG-CoA reductase inhibitors (statins) decrease MMP-3 and MMP-9 concentrations in abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2005;30(3): 259–262.

  33. 33.

    Boodhwani M, Mieno S, Feng J, et al. Atorvastatin impairs the myocardial angiogenic response to chronic ischemia in normocholesterolemic swine. J Thorac Cardiovasc Surg. 2008;135(1): 117–122.

  34. 34.

    Cho SJ, Kim JS, Kim JM, Lee JY, Jung HC, Song IS. Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in mice. Int J Cancer. 2008;123(4): 951–957.

  35. 35.

    Mori H, Sawairi M, Nakagawa M, Itoh N, Wada K, Tamaya T. Peritoneal fluid interleukin-1 beta and tumor necrosis factor in patients with benign gynecologic disease. Am J Reprod Immunol. 1991;26(2): 62–67.

  36. 36.

    Pellicer A, Albert C, Mercader A, Bonilla-Musoles F, Remohi J, Simon C. The follicular and endocrine environment in women with endometriosis: local and systemic cytokine production. Fertil Steril. 1998;70(3): 425–431.

  37. 37.

    Ozbek E, Cekmen M, Ilbey YO, Simsek A, Polat EC, Somay A. Atorvastatin prevents gentamicin-induced renal damage in rats through the inhibition of p38-MAPK and NF-kappaB pathways. Ren Fail. 2009;31(5): 382–392.

  38. 38.

    Zelvyte I, Dominaitiene R, Crisby M, Janciauskiene S. Modulation of inflammatory mediators and PPARgamma and NFkappaB expression by pravastatin in response to lipoproteins in human monocytes in vitro. Pharmacol Res. 2002;45(2): 147–154.

  39. 39.

    Foyouzi N, Berkkanoglu M, Arici A, Kwintkiewicz J, Izquierdo D, Duleba AJ. Effects of oxidants and antioxidants on proliferation of endometrial stromal cells. Fertil Steril. 2004;82(suppl 3): 1019–1022.

  40. 40.

    Franzoni F, Quinones-Galvan A, Regoli F, Ferrannini E, Galetta F. A comparative study of the in vitro antioxidant activity of statins. Int J Cardiol. 2003;90(2–3): 317–321.

Download references

Author information

Correspondence to Aydin Arici MD.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cakmak, H., Basar, M., Seval-Celik, Y. et al. Statins Inhibit Monocyte Chemotactic Protein 1 Expression in Endometriosis. Reprod. Sci. 19, 572–579 (2012) doi:10.1177/1933719111430998

Download citation

Keywords

  • endometriosis
  • statin
  • MCP-1
  • inflammation