| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Medical Research Council Toxicology Unit, University of Leicester, Leicester, United Kingdom; and
Division of Cardiology, University of Leicester, Glenfield General Hospital, Leicester, United Kingdom
Statins, which inhibit 3-hydroxy-3-methylglutaryl CoA reductase, have been shown recently to promote proinflammatory responses. We show in this study that both atorvastatin and simvastatin induced proinflammatory responses in mitogen-activated PBMCs by increasing the number of T cells secreting IFN-
. This is abolished by the presence of mevalonate, suggesting that statins act specifically by blocking the mevalonate pathway for cholesterol synthesis to promote the proinflammatory response. Both statins at low concentrations induced a dose-dependent increase in the number of IFN--secreting T cells in mitogen-activated PBMCs, whereas at higher concentrations the effect was abolished. The proinflammatory effect of statins was not seen in purified T cells per se activated with mitogen. However, conditioned medium derived from statin-treated PBMCs enhanced the number of IFN--secreting cells in activated purified T cells. This effect was not blocked by mevalonate, but was abolished by neutralizing Abs to IL-18 and IL-12. Similarly, the up-regulation of IFN--secreting T cells in PBMCs costimulated with statins and mitogens was blocked by the neutralizing anti-IL-18 and anti-IL-12. We showed that simvastatin stimulates the secretion of IL-18 and IL-1
in monocytes. Active caspase-1, which is required for the processing and secretion of IL-18 and IL-1, was activated in simvastatin-treated monocytes. This was blocked by mevalonate and the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone. Taken together, the proinflammatory response mediated by statins in activated PBMCs is mediated mainly via the activation of caspase-1 and IL-18 secretion in the monocytes and to a lesser extent by IL-12.
This article has been cited by other articles:
|
|
 |
|
  F. Montecucco, F. Burger, G. Pelli, N. K. Poku, C. Berlier, S. Steffens, and F. Mach Statins inhibit C-reactive protein-induced chemokine secretion, ICAM-1 upregulation and chemotaxis in adherent human monocytes Rheumatology, March 1, 2009; 48(3): 233 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Schmeer, A. Gamez, S. Tausch, O. W. Witte, and S. Isenmann Statins Modulate Heat Shock Protein Expression and Enhance Retinal Ganglion Cell Survival after Transient Retinal Ischemia/Reperfusion In Vivo Invest. Ophthalmol. Vis. Sci., November 1, 2008; 49(11): 4971 - 4981. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Lee, H. Qin, and E. N. Benveniste Simvastatin inhibits IFN-{gamma}-induced CD40 gene expression by suppressing STAT-1{alpha} J. Leukoc. Biol., August 1, 2007; 82(2): 436 - 447. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Santic, R. Asare, M. Doric, and Y. Abu Kwaik Host-Dependent Trigger of Caspases and Apoptosis by Legionella pneumophila Infect. Immun., June 1, 2007; 75(6): 2903 - 2913. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Asare, M. Santic, I. Gobin, M. Doric, J. Suttles, J. E. Graham, C. D. Price, and Y. Abu Kwaik Genetic Susceptibility and Caspase Activation in Mouse and Human Macrophages Are Distinct for Legionella longbeachae and L. pneumophila Infect. Immun., April 1, 2007; 75(4): 1933 - 1945. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Simon and J. W. M. van der Meer Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2007; 292(1): R86 - R98. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
