Hydroxymethylglutaryl-coenzyme A reductase inhibition stimulates caspase-1activity and Th1-cytokine release in peripheral blood mononuclear cells

T cells are prominent components of both early and late atherosclerotic les ions and the role of Th1/Th2 cells subsets in the evolution and rupture of the plaque is currently under investigation. Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, exert actions beyond that of simply lowering cholesterol levels, and some effects on immune fun ction have been reported. We studied in vitro the effects of fluvastatin on Th1/Th2 cytokine release in relation to caspase-1 activation, in human per ipheral-blood mononuclear cells (PBMC) stimulated or not with Mycobacterium tuberculosis. Fluvastatin treatment resulted in the activation of caspase- 1 and in a small secretion of interleukin (IL)-1 beta, IL-18, and IFN gamma (Th1). In the presence of bacteria, the release of these cytokines was hig hly increased by the statin in a synergistic way. By contrast, production o f IL-12, IL-IO and IL-4 were unaffected by the statin. Not only did mevalon ate abolish the effects of the statin but it also prevented the caspase-1 a ctivation induced by the bacteria, suggesting the involvement of isoprenoid s in the response to M. tuberculosis. It is proposed that inhibition of HMG -CoA reductase may be immunoprotective by enhancing the Th1 response, which has therapeutical potential not only in atherosclerosis but also in infect ious diseases. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.