Published online before print October 16, 2003, doi: 10.1161/01.RES.0000101298.76864.14
© 2003 American Heart Association, Inc.
Molecular Medicine |
Inhibition of Hydroxymethylglutaryl-Coenzyme A Reductase Reduces Th1 Development and Promotes Th2 Development
From the Health Service Center (R.H.-T., Y.U., H.N., T.T.) and Department of Medicine (Y.U., H.N., T.F., T.T.), University of Tokyo, Tokyo, Japan; Department of Bioregulation (K.K., K.S., T.K.), Mie University School of Medicine, Mie, Japan; and Department of Clinical Laboratory Medicine and Institute of Medical Science (A.N.), Dokkyo University School of Medicine, Tochigi, Japan.
Correspondence to Takuma Kato, PhD, Department of Bioregulation, Mie University School of Medicine, 2-174 Edobashi, Tsu-shi, Mie, 514-8507, Japan. 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
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