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Pharmacological inhibitors of the mevalonate pathway activate pro-IL-1 processing and IL-1 release by human monocytes

Benoit Massonnet1, Sylvain Normand, Reinhard Moschitz

  • 1Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, EA 4331, Université de Poitiers, Poitiers, France.

European Cytokine Network
|October 15, 2009
PubMed
Abstract

Insights

Statins, by inhibiting the mevalonate pathway, specifically increase pro-inflammatory cytokines like IL-1alpha, IL-1beta, and IL-18. This occurs via enhanced caspase-1 activity, linking statin use to inflammation modulation.

Area of Science:

  • Biochemistry
  • Immunology
  • Pharmacology

Background:

  • The impact of statins (3-hydroxy-3-methylglutaryl coenzyme A reductase-HMGR-inhibitors) on inflammatory responses is not fully understood.
  • HMGR plays a key role in the mevalonate pathway, upstream of cholesterol biosynthesis.
  • Investigating the mevalonate pathway's influence on cytokine production is crucial for understanding statin's effects on inflammation.

Purpose of the Study:

  • To determine the specific cytokine signature induced by simvastatin treatment in peripheral blood mononuclear cells (PBMCs) and THP-1 cells.
  • To elucidate the link between pharmacological inhibition of the mevalonate pathway and cellular inflammatory responses.
  • To identify how statin-mediated HMGR inhibition affects cytokine production.

Main Methods:

  • Culturing human PBMCs and THP-1 cells with HMGR inhibitors (simvastatin), geranylgeranyltransferase inhibitor (GGTI-298), farnesyltransferase inhibitor (FTI-277), and caspase-1 inhibitor (Z-VAD(Ome)-FMK).
  • Assessing cytokine production, caspase-1 activity, IL-1beta mRNA levels, and Rac-1 activity post-culture.
  • Utilizing lipopolysaccharide (LPS) to activate PBMCs and THP-1 cells for cytokine release studies.

Main Results:

  • Simvastatin treatment specifically enhanced the release of IL-1alpha, IL-1beta, and IL-18, while inhibiting IL-1ra production in LPS-activated cells.
  • Simvastatin increased caspase-1 activity, crucial for IL-1beta and IL-18 maturation, without altering pro-IL-1beta expression.
  • Geranylgeranylation inhibition by GGTI-298 also boosted IL-1-family cytokine production, indicating its role in caspase-1 activation. Simvastatin also increased Rac-1 activity.

Conclusions:

  • Pharmacological inhibition of the mevalonate pathway using statins distinctly induces pro-inflammatory cytokines of the IL-1 family.
  • The maturation of IL-1beta and IL-18 is directly promoted by caspase-1 activation, while IL-1alpha maturation is indirectly affected.
  • These findings highlight a specific inflammatory cytokine signature associated with statin therapy, mediated by caspase-1-dependent mechanisms.

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