Published online before print October 16, 2003, doi: 10.1161/01.RES.0000101298.76864.14
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on September 19, 2002
Revised on November 2, 2003
Accepted on November 2, 2003
Inhibition of Hydroxymethylglutaryl-Coenzyme A Reductase Reduces Th1 Development and Promotes Th2 Development
Rie Hakamada-Taguchi ;
From the Health Service Center (R.H.-T., Y.U., H.N., T.T.) and Department of Medicine (R.H.-T., Y.U., H.N., T.F., T.T.), University of Tokyo; Department of Bioregulation (K.K., K.S., T.K.), Mie University School of Medicine; and Department of Clinical Laboratory Medicine and Institute of Medical Science (A.N.), Dokkyo University School of Medicine, Tochigi, Japan.
* To whom correspondence should be addressed. E-mail: katotaku{at}doc.medic.mie-u.ac.jp.
Several prospective clinical studies have indicated that hydroxymethylglutaryl-coenzyme A reductase inhibitors, statins, prevent cardiovascular events in part through their antiinflammatory properties. Because inflammation is positively and negatively regulated by T helper (Th) 1 cells and Th2 cells, respectively, we examined the effects of statins on the Th polarization in vitro and in vivo. Here we demonstrated that the statins tested, ie, cerivastatin, simvastatin, lovastatin, and atorvastatin, promoted Th2 polarization through both inhibition of Th1 development and augmentation of Th2 development of CD4+ T cells primed in vitro with anti-CD3 antibody and splenic antigen-presenting cells. Cerivastatin exerted most potent effect on modulation of Th1/Th2 development, and the effect was completely abrogated by an addition of mevalonate. Consistent with in vitro experiments, cerivastatin treatment decreased IFN-
production of lymph node cells from mice immunized with ovalbumin emulsified in complete Freund’s adjuvant, indicating that Th1 development is also suppressed in an in vivo proinflammatory environment. In this murine model, cerivastatin significantly reduced mesangial matrix expansion of glomeruli in the kidney and attenuated proteinuria. The decrease of glomerular sclerosis by cerivastatin treatment was positively related to the suppression of interferon (IFN)--producing Th1 response in draining lymph node cells. Hence, these findings strongly suggest that statins’ inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase regulates Th1/Th2 polarization in vivo and such a mechanism possibly plays a pathophysiological role in immune-related glomerular injury.
Key words: statins • 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors • Th1/Th2 • inflammation • glomerular sclerosis
This article has been cited by other articles:
 |
|
 |
|
  T. Morris, M. Stables, A. Hobbs, P. de Souza, P. Colville-Nash, T. Warner, J. Newson, G. Bellingan, and D. W. Gilroy Effects of Low-Dose Aspirin on Acute Inflammatory Responses in Humans J. Immunol., August 1, 2009; 183(3): 2089 - 2096. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Khan, R. M. Gallo, G. J. Renukaradhya, W. Du, J. Gervay-Hague, and R. R. Brutkiewicz Statins Impair CD1d-Mediated Antigen Presentation through the Inhibition of Prenylation J. Immunol., April 15, 2009; 182(8): 4744 - 4750. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. K Rubin Statins for the treatment of asthma: a discovery well, dry hole or just snake oil Thorax, January 1, 2009; 64(1): 4 - 5. [Full Text] [PDF]
|
|
|
|
|
|
M Imamura, K Okunishi, H Ohtsu, K Nakagome, H Harada, R Tanaka, K Yamamoto, and M Dohi Pravastatin attenuates allergic airway inflammation by suppressing antigen sensitisation, interleukin 17 production and antigen presentation in the lung Thorax, January 1, 2009; 64(1): 44 - 49. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Hamilton, K. C. Goldberg, E. A. Platz, and S. J. Freedland The Influence of Statin Medications on Prostate-specific Antigen Levels J Natl Cancer Inst, November 5, 2008; 100(21): 1511 - 1518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. R. S. Packard, S. Schlegel, D. Senouf, F. Burger, P. Sigaud, T. Perneger, C.-A. Siegrist, and F. Mach Atorvastatin Treatment and Vaccination Efficacy J. Clin. Pharmacol., August 1, 2007; 47(8): 1022 - 1027. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Link, T. Ayadhi, M. Bohm, and G. Nickenig Rapid immunomodulation by rosuvastatin in patients with acute coronary syndrome Eur. Heart J., December 2, 2006; 27(24): 2945 - 2955. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E Hothersall, C McSharry, and N C Thomson Potential therapeutic role for statins in respiratory disease. Thorax, August 1, 2006; 61(8): 729 - 734. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Arora, L. Chen, M. Paglia, I. Gallagher, J. E. Allen, Y. M. Vyas, A. Ray, and P. Ray Simvastatin promotes Th2-type responses through the induction of the chitinase family member Ym1 in dendritic cells PNAS, May 16, 2006; 103(20): 7777 - 7782. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Yilmaz, C. Reiss, A. Weng, I. Cicha, C. Stumpf, A. Steinkasserer, W. G. Daniel, and C. D. Garlichs Differential effects of statins on relevant functions of human monocyte-derived dendritic cells J. Leukoc. Biol., March 1, 2006; 79(3): 529 - 538. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Brugaletta, L M Biasucci, M Pinnelli, G Biondi-Zoccai, G Di Giannuario, G Trotta, G Liuzzo, and F Crea Novel anti-inflammatory effect of statins: reduction of CD4+CD28null T lymphocyte frequency in patients with unstable angina Heart, February 1, 2006; 92(2): 249 - 250. [Full Text] [PDF]
|
|
|
|
 |
|
 X. Cheng, Y.-H. Liao, J. Zhang, B. Li, H. Ge, J. Yuan, M. Wang, B. Lu, Y. Liu, and Y. Cheng Effects of Atorvastatin on Th polarization in patients with acute myocardial infarction Eur J Heart Fail, December 1, 2005; 7(7): 1099 - 1104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K. Ray and C. P. Cannon The Potential Relevance of the Multiple Lipid-Independent (Pleiotropic) Effects of Statins in the Management of Acute Coronary Syndromes J. Am. Coll. Cardiol., October 18, 2005; 46(8): 1425 - 1433. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Gullu, R. Emral, M. Bastemir, A. B Parkes, and J. H Lazarus In vivo and in vitro effects of statins on lymphocytes in patients with Hashimoto's thyroiditis Eur. J. Endocrinol., July 1, 2005; 153(1): 41 - 48. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Yamakuchi, J. J.M. Greer, S. J. Cameron, K. Matsushita, C. N. Morrell, K. Talbot-Fox, W. M. Baldwin III, D. J. Lefer, and C. J. Lowenstein HMG-CoA Reductase Inhibitors Inhibit Endothelial Exocytosis and Decrease Myocardial Infarct Size Circ. Res., June 10, 2005; 96(11): 1185 - 1192. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E C Jury and M R Ehrenstein Statins: immunomodulators for autoimmune rheumatic disease? Lupus, March 1, 2005; 14(3): 192 - 196. [Abstract] [PDF]
|
|
|
|
 |
|
 C. Bucca, A. Marsico, E. Panaro, P. Bigo, and L. Brussino Statins and Nasal Polyps Ann Intern Med, February 15, 2005; 142(4): 310 - 311. [Full Text] [PDF]
|
|
|
|
 |
|
 I B McInnes, D W McCarey, and N Sattar Do statins offer therapeutic potential in inflammatory arthritis? Ann Rheum Dis, December 1, 2004; 63(12): 1535 - 1537. [Full Text] [PDF]
|
|
|
|
 |
|
 R. W. Azuma, J.-i. Suzuki, M. Ogawa, H. Futamatsu, N. Koga, Y. Onai, H. Kosuge, and M. Isobe HMG-CoA reductase inhibitor attenuates experimental autoimmune myocarditis through inhibition of T cell activation Cardiovasc Res, December 1, 2004; 64(3): 412 - 420. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Shimada, K. Miyauchi, H. Daida, S. Kinlay, P. Libby, P. Ganz, For the MIRACL Study Investigators, G. G. Schwartz, A. G. Olsson, N. Rifai, et al. Early Intervention With Atorvastatin Modulates Th1/Th2 Imbalance in Patients With Acute Coronary Syndrome: From Bedside to Bench * Response Circulation, May 11, 2004; 109(18): e213 - e214. [Full Text] [PDF]
|
|