Immune Modulatory Effects of Hypercholesterolemia: Can Atorvastatin Convert the Detrimental Effect of Hypercholesterolemia on the Immune System?
Abstract
Many observations showed that hypercholesterolemia can disrupt immune response. Statin drugs that were used for the treatment of hypercholesterolemia patients can interfere in the regulation of the immune response and cytokine secretion. The primary aim of the current study was to investigate the immune response among treatment-naïve patients with hypercholesterolemia and healthy subjects. The secondary goal of the study was to determine whether atorvastatin can reverse the detrimental effect of hypercholesterolemia on the immune system. Peripheral blood mononuclear cells (PBMCs) were isolated from 50 patients afflicted with hypercholesterolemia who were treatment-naïve along with 50 sex/age-matched hypercholesterolemia patients receiving atorvastatin, and 50 sex/age-matched healthy subjects. Quantitative PCR and ELISA methods were used for gene and protein expression analysis of T helper 1 (Th1) and Th2 related cytokines. Additionally, the expression of the cluster of differentiation (CD) markers on T, B, and natural killer (NK) cells was measured by flow cytometry method. The results showed that hypercholesterolemia and atorvastatin down-regulated the expression of Th1-related cytokines and elevated the levels of Th2-related cytokines. The expression of cell surface markers, CD25 and CD69, was significantly decreased in the treatment-naïve, and atorvastatin groups. It seems that atorvastatin is not able to repair the deleterious effects of hypercholesterolemia on the immune system. Moreover, elevated levels of cholesterol along with the administration of atorvastatin tilt the Th1/Th2 balance in favor of Th2 and reduce T cell activation.
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14. Coward W, Chow SC. Effect of atorvastatin on TH 1 and TH 2 cytokine secreting cells during T cell activation and differentiation. Atherosclerosis 2006;186(2):302-9.
15. Rando RR. Chemical biology of protein isoprenylation/methylation. Biochim Biophys Acta 1996;1300(1):5-16.
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17. Shimada K, Miyauchi K, Daida H. Early intervention with atorvastatin modulates TH1/TH2 imbalance in patients with acute coronary syndrome: from bedside to bench. Circulation 2004;109(18):e213-e4.
18. Földes G, Anker SD, von Haehling S. Atorvastatin modulates Th1/Th2 response in patients with chronic heart failure. Journal of cardiac failure 2009; 15(6):551.
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24. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000;6(12):1399-402.
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27. Dunn SE, Youssef S, Goldstein MJ, Prod'homme T, Weber MS, Zamvil SS, et al. Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin. J Exp Med 2006;203(2):401-12.
28. Jiang T, Zhou C, Ren S. Role of IL-2 in cancer immunotherapy. Oncoimmunology 2016;5(6):e1163462.
29. Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol 2006;6(11):836-48.
30. Waters JP, Pober JS, Bradley JR. Tumour necrosis factor and cancer. J Pathol 2013;230(3):241-8.
31. Takatsu K, Kouro T, Nagai Y. Interleukin 5 in the link between the innate and acquired immune response. Adv Immunol 2009;101:191-236.
32. Kraakman MJ, Dragoljevic D, Kammoun HL, Murphy AJ. Is the risk of cardiovascular disease altered with anti‐inflammatory therapies? Insights from rheumatoid arthritis. Clin Transl Immunology 2016;5(5):e84.
33. Proto JD, Doran AC, Subramanian M, Wang H, Zhang M, Sozen E, et al. Hypercholesterolemia induces T cell expansion in humanized immune mice. J Clin Invest 2018;128(6):2370-5.
34. Muldoon MF, Marsland A, Flory JD, Rabin BS, Whiteside TL, Manuck SB. Immune system differences in men with hypo-or hypercholesterolemia. Clin Immunol Immunopathol 1997;84(2):145-9.
35. Guo X, Yan C, Li H, Huang W, Shi X, Huang M, et al. Lipid-dependent conformational dynamics underlie the functional versatility of T-cell receptor. Cell Res 2017;27(4):505-25.
36. Blank N, Schiller M, Krienke S, Busse F, Schätz B, Ho AD, et al. Atorvastatin inhibits T cell activation through 3-hydroxy-3-methylglutaryl coenzyme A reductase without decreasing cholesterol synthesis. J Immunol 2007;179(6):3613-21.
37. Wu L-H, Wan Y-L, Xie H-Y, Zhang W-J, Zheng S-S. Immunosuppression in human peripheral blood T lymphocytes by fluvastatin. Acta biochimica et biophysica Sinica. Acta Biochim Biophys Sin (Shanghai)2004;36(10):649-55.
38. Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J, Bruns C, et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 2001;7(6):687-92.
39. Kanda H, Yokota K, Kohno C, Sawada T, Sato K, Yamaguchi M, et al. Effects of low-dosage simvastatin on rheumatoid arthritis through reduction of Th1/Th2 and CD4/CD8 ratios. Mod Rheumatol 2007;17(5):364-8.
40. McBride JA, Striker R. Imbalance in the game of T cells: What can the CD4/CD8 T-cell ratio tell us about HIV and health? PLoS Pathog 2017;13(11):e1006624.
2. Lei L, Li H, Yan F, Xiao Y. Hyperlipidemia impaired innate immune response to periodontal pathogen Porphyromonas gingivalis in apolipoprotein E knockout mice. PLoS One 2013;8(8):e71849.
3. Dansky HM, Charlton SA, Harper MM, Smith JD. T and B lymphocytes play a minor role in atherosclerotic plaque formation in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci U S A 1997;94(9):4642-6.
4. Zhou X, Paulsson G, Stemme S, Hansson GK. Hypercholesterolemia is associated with a T helper (Th) 1/Th2 switch of the autoimmune response in atherosclerotic apo E-knockout mice. J Clin Invest 1998;101(8):1717-25.
5. Font-Burgada J, Sun B, Karin M. Obesity and cancer: the oil that feeds the flame. Cell Metab 2016;23(1):48-62.
6. Tie G, Yan J, Khair L, Messina JA, Deng A, Kang J, et al. Hypercholesterolemia increases colorectal cancer incidence by reducing production of NKT and γδ T cells from hematopoietic stem cells. Cancer res 2017;77(9):2351-62.
7. Silverstein DM. Indications and outcome of treatment of hyperlipidemia in pediatric allograft recipients. Pediatr Transplant 2003;7(1):7-10.
8. Ramkumar S, Raghunath A, Raghunath S. Statin therapy: review of safety and potential side effects. Acta Cardiologica Sinica 2016; 32(6):631.
9. Tomaszewski M, Stępień KM, Tomaszewska J, Czuczwar SJ. Statin-induced myopathies. Pharmacol Rep 2011;63(4):859-66.
10. Weitz-Schmidt G. Statins as anti-inflammatory agents. Trends Pharmacol Sci 2002;23(10):482-7.
11. Yilmaz A, Reiss C, Weng A, Cicha I, Stumpf C, Steinkasserer A, et al. Differential effects of statins on relevant functions of human monocyte-derived dendritic cells. J Leukoc Biol 2006;79(3):529-38.
12. Cheng X, Ding Y, Xia C, Tang T, Yu X, Xie J, et al. Atorvastatin modulates Th1/Th2 response in patients
with chronic heart failure. J Card Fail 2009;15(2):158-62.
13. Mowla K, Rajai E, Ghorbani A, Dargahi-Malamir M, Bahadoram M, Mohammadi S. Effect of atorvastatin on the disease activity and severity of rheumatoid arthritis: double-blind randomized controlled trial. J Clin Diagn Res 2016;10(5):OC32-6.
14. Coward W, Chow SC. Effect of atorvastatin on TH 1 and TH 2 cytokine secreting cells during T cell activation and differentiation. Atherosclerosis 2006;186(2):302-9.
15. Rando RR. Chemical biology of protein isoprenylation/methylation. Biochim Biophys Acta 1996;1300(1):5-16.
16. Leung BP, Sattar N, Crilly A, Prach M, McCarey DW, Payne H, et al. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol 2003;170(3):1524-30.
17. Shimada K, Miyauchi K, Daida H. Early intervention with atorvastatin modulates TH1/TH2 imbalance in patients with acute coronary syndrome: from bedside to bench. Circulation 2004;109(18):e213-e4.
18. Földes G, Anker SD, von Haehling S. Atorvastatin modulates Th1/Th2 response in patients with chronic heart failure. Journal of cardiac failure 2009; 15(6):551.
19. Youssef S, Stüve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 2002;420(6911):78-84.
20. Zeiser R. Immune modulatory effects of statins. Immunology 2018;154(1):69-75.
21. Rodríguez‐Perea A, Rojas M, Velilla‐Hernández P. High concentrations of atorvastatin reduce in‐vitro function of conventional T and regulatory T cells. Clin Exp Immunol 2019; 196(2):237-48.
22. Ghittoni R, Enea Lazzerini P, Laghi Pasini F, Baldari CT. T lymphocytes as targets of statins: molecular mechanisms and therapeutic perspectives. Inflamm Allergy Drug Targets 2007;6(1):3-16.
23. Shimada K, Park JK, Daida H. T helper 1/T helper 2 balance and HMG-CoA reductase inhibitors in acute coronary syndrome: statins as immunomodulatory agents? Eur Heart J 2006; 27(24):2916-8.
24. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000;6(12):1399-402.
25. Weber MS, Prod’homme T, Youssef S, Dunn SE, Steinman L, Zamvil SS. Neither T-helper type 2 nor Foxp3+ regulatory T cells are necessary for therapeutic benefit of atorvastatin in treatment of central nervous system autoimmunity. J Neuroinflammation 2014;11(1):29.
26. Link A, Ayadhi T, Böhm M, Nickenig G. Rapid immunomodulation by rosuvastatin in patients with acute coronary syndrome. Eur Heart J 2006;27(24):2945-55.
27. Dunn SE, Youssef S, Goldstein MJ, Prod'homme T, Weber MS, Zamvil SS, et al. Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin. J Exp Med 2006;203(2):401-12.
28. Jiang T, Zhou C, Ren S. Role of IL-2 in cancer immunotherapy. Oncoimmunology 2016;5(6):e1163462.
29. Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol 2006;6(11):836-48.
30. Waters JP, Pober JS, Bradley JR. Tumour necrosis factor and cancer. J Pathol 2013;230(3):241-8.
31. Takatsu K, Kouro T, Nagai Y. Interleukin 5 in the link between the innate and acquired immune response. Adv Immunol 2009;101:191-236.
32. Kraakman MJ, Dragoljevic D, Kammoun HL, Murphy AJ. Is the risk of cardiovascular disease altered with anti‐inflammatory therapies? Insights from rheumatoid arthritis. Clin Transl Immunology 2016;5(5):e84.
33. Proto JD, Doran AC, Subramanian M, Wang H, Zhang M, Sozen E, et al. Hypercholesterolemia induces T cell expansion in humanized immune mice. J Clin Invest 2018;128(6):2370-5.
34. Muldoon MF, Marsland A, Flory JD, Rabin BS, Whiteside TL, Manuck SB. Immune system differences in men with hypo-or hypercholesterolemia. Clin Immunol Immunopathol 1997;84(2):145-9.
35. Guo X, Yan C, Li H, Huang W, Shi X, Huang M, et al. Lipid-dependent conformational dynamics underlie the functional versatility of T-cell receptor. Cell Res 2017;27(4):505-25.
36. Blank N, Schiller M, Krienke S, Busse F, Schätz B, Ho AD, et al. Atorvastatin inhibits T cell activation through 3-hydroxy-3-methylglutaryl coenzyme A reductase without decreasing cholesterol synthesis. J Immunol 2007;179(6):3613-21.
37. Wu L-H, Wan Y-L, Xie H-Y, Zhang W-J, Zheng S-S. Immunosuppression in human peripheral blood T lymphocytes by fluvastatin. Acta biochimica et biophysica Sinica. Acta Biochim Biophys Sin (Shanghai)2004;36(10):649-55.
38. Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J, Bruns C, et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 2001;7(6):687-92.
39. Kanda H, Yokota K, Kohno C, Sawada T, Sato K, Yamaguchi M, et al. Effects of low-dosage simvastatin on rheumatoid arthritis through reduction of Th1/Th2 and CD4/CD8 ratios. Mod Rheumatol 2007;17(5):364-8.
40. McBride JA, Striker R. Imbalance in the game of T cells: What can the CD4/CD8 T-cell ratio tell us about HIV and health? PLoS Pathog 2017;13(11):e1006624.
| Files | ||
| Issue | Vol 18, No 5 (2019) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v18i5.1925 | |
| PMID | 32245299 | |
| Keywords | ||
| Atorvastatin Cytokine Hypercholesterolemia Immune response | ||
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How to Cite
1.
Emruzi Z, Babaheidarian P, Arshad M, Stockinger H, Ahangari G. Immune Modulatory Effects of Hypercholesterolemia: Can Atorvastatin Convert the Detrimental Effect of Hypercholesterolemia on the Immune System?. Iran J Allergy Asthma Immunol. 2019;18(5):554-566.
