The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines

Flavio Leoni, Andrea Zaliani, Giorgio Bertolini, Giulia Porro, Paolo Pagani, Pietro Pozzi, Giancarlo Donà, Gianluca Fossati, Silvano Sozzani, Tania Azam, Philip Bufler, Giamila Fantuzzi, Igor Goncharov, Soo Hyun Kim, Benjamin J. Pomerantz, Leonid L. Reznikov, Britta Siegmund, Charles A. Dinarello, Paolo Mascagni

Research output: Contribution to journalArticlepeer-review

Abstract

Suberoylanilide hydroxamic acid (SAHA) is a hydroxamic acid-containing hybrid polar molecule; SAHA specifically binds to and inhibits the activity of histone deacetylase. Although SAHA, like other inhibitors of histone deacetylase, exhibits antitumor effects by increasing expression of genes regulating tumor survival, we found that SAHA reduces the production of proinflammatory cytokines in vivo and in vitro. A single oral administration of SAHA to mice dose-dependently reduced circulating TNF-α, IL-1-β, IL-6, and IFN-γ induced by lipopolysaccharide (LPS). Administration of SAHA also reduced hepatic cellular injury in mice following i.v. injection of Con A. SAHA inhibited nitric oxide release in mouse macrophages stimulated by the combination of TNF-α plus IFN-γ. Human peripheral blood mononuclear cells stimulated with LPS in the presence of SAHA released less TNF-α, IL-1-β, IL-12, and IFN-γ (50% reduction at 100-200 nM). The production of IFN-γ stimulated by IL-18 plus IL-12 was also inhibited by SAHA (85% at 200 nM). However, SAHA did not affect LPS-induced synthesis of the IL-1-β precursor, the IL-1 receptor antagonist, or the chemokine IL-8. In addition, IFN-γ induced by anti-CD3 was not suppressed by SAHA. Steady-state mRNA levels for LPS-induced TNF-α and IFN-γ in peripheral blood mononuclear cells were markedly decreased, whereas IL-8 and IL-1-β mRNA levels were unaffected. Because SAHA exhibits antiinflammatory properties in vivo and in vitro, inhibitors of histone deacetylase may stimulate the expression of genes that control the synthesis of cytokines and nitric oxide or hyperacetylate other targets.

Original languageEnglish
Pages (from-to)2995-3000
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number5
DOIs
Publication statusPublished - Mar 5 2002

ASJC Scopus subject areas

  • Genetics
  • General

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