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

Atherosclerosis. 2000 Dec;153(2):303-13. doi: 10.1016/s0021-9150(00)00417-2.


T cells are prominent components of both early and late atherosclerotic lesions 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 function have been reported. We studied in vitro the effects of fluvastatin on Th1/Th2 cytokine release in relation to caspase-1 activation, in human peripheral-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)-1beta, IL-18, and IFNgamma (Th1). In the presence of bacteria, the release of these cytokines was highly increased by the statin in a synergistic way. By contrast, production of IL-12, IL-10 and IL-4 were unaffected by the statin. Not only did mevalonate abolish the effects of the statin but it also prevented the caspase-1 activation induced by the bacteria, suggesting the involvement of isoprenoids 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 infectious diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caspase 1 / metabolism*
  • Cytokines / metabolism*
  • Fatty Acids, Monounsaturated / pharmacology
  • Fluvastatin
  • Humans
  • Hydroxymethylglutaryl CoA Reductases / metabolism*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Indoles / pharmacology
  • Leukocytes, Mononuclear / metabolism*
  • Th1 Cells / metabolism


  • Cytokines
  • Fatty Acids, Monounsaturated
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Indoles
  • Fluvastatin
  • Hydroxymethylglutaryl CoA Reductases
  • Caspase 1