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

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-alpha, IL-1-beta, IL-6, and IFN-gamma 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-alpha plus IFN-gamma. Human peripheral blood mononuclear cells stimulated with LPS in the presence of SAHA released less TNF-alpha, IL-1-beta, IL-12, and IFN-gamma (50% reduction at 100-200 nM). The production of IFN-gamma 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-beta precursor, the IL-1 receptor antagonist, or the chemokine IL-8. In addition, IFN-gamma induced by anti-CD3 was not suppressed by SAHA. Steady-state mRNA levels for LPS-induced TNF-alpha and IFN-gamma in peripheral blood mononuclear cells were markedly decreased, whereas IL-8 and IL-1-beta 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.

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@article{Leoni2002TheAH, title={The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines.}, author={Flavio Leoni and Andrea Zaliani and Giorgio Bertolini and Giulia Porro and P. Pagani and Pietro Pozzi and Giancarlo Don{\`a} and Gianluca Fossati and Silvano Sozzani and Tania Azam and Philip Bufler and Giamila Fantuzzi and Igor Goncharov and Soo Hyun Kim and Benjamin J Pomerantz and Leonid L. Reznikov and Britta Siegmund and Charles Anthony Dinarello and Paolo Mascagni}, journal={Proceedings of the National Academy of Sciences of the United States of America}, year={2002}, volume={99 5}, pages={2995-3000} }