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

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

doi:10.1073/pnas.052702999

Cited by 473 publications

(471 citation statements)

References 37 publications

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“…In contrast, comprehensive evidence from experiments with isolated lungs and those with intact animals suggest that on the protein level the overall effect of TSA in vivo tends to be anti-inflammatory. This conclusion is corroborated by the antiinflammatory action of HDACi in experimental models of acute lung injury (this study), asthma [20], sepsis [21], arthritis [22,38], autoimmune encephalomyelitis [39], colitis [40] and concanavalin-A-induced hepatitis [21]. From the present study we suggest that the discrepancies between the in vivo and perfused lung studies on the one hand, and the cell culture studies on the other may be ascribed to the focus on M A N U S C R I P T has not revealed a pattern that correlated with the current findings (data not shown).…”

Section: Discussionsupporting

confidence: 75%

“…4b. For instance, in the murine peritonitis model, the effect of TSA on MIP-2-release was dose-dependent, as lower HDACi concentrations reduced and higher concentrations increased MIP-2α production [21]. In this regard it may be of relevance that MIP-2 α differs from other chemokines, because it can be stored inside cells and thus its release need not always depend on de novo synthesis [36].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, in other animal models of inflammation HDACi reduced the endotoxin-induced serum levels of TNF, IL-1, IL-6 and IFNγ in a sepsis model [21] and IL-6 and IL-1β levels in an arthritis M A N U S C R I P T…”

Section: Introductionmentioning

confidence: 99%

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Conserved responses to trichostatin A in rodent lungs exposed to endotoxin or stretch

Dombrowsky

Barrenschee

Kunze

et al. 2009

Pulmonary Pharmacology & Therapeutics

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Histone deacetylase (HDAC) isoenzymes have been suggested as possible drug targets in pulmonary cancer and in inflammatory lung diseases such as asthma and COPD. Whether HDAC inhibition is pro-or anti-inflammatory is under debate.To further examine this clinically relevant paradigm, we analyzed 8 genes that are upregulated by two pro-inflammatory stimuli, i.e. endotoxin and mechanical stress (overventilation), in isolated rat and mouse lungs, respectively. We studied the effect of the HDAC inhibitor trichostatin A (TSA) under control conditions, in response to endotoxin and overventilation, and on the effects of the steroid dexamethasone.TSA affected gene expression largely independent of the stimulus (endotoxin, overventilation) and the species (rat, mouse) leading to upregulation of some genes (Tnf, Cxcl2) and downregulation of others (Cxcl10, Timp1, Selp, Il6). At the protein level, TSA reduced the stimulated release of TNF, MIP-2α and IL-6, indicating that TSA may affect protein translation independent from gene transcription. In general, the anti-inflammatory effects of TSA on gene expression and protein release were additive to that of dexamethasone, suggesting that both drugs employ different mechanisms.We conclude that pro-inflammatory stimuli induce distinct sets of genes that are regulated by HDAC in a diverse, but consistent manner across two rodent species.The present findings together with previous in vivo studies suggest that the effect of HDAC inhibition in the intact lung is in part anti-inflammatory.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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Conserved responses to trichostatin A in rodent lungs exposed to endotoxin or stretch

Dombrowsky

Barrenschee

Kunze

et al. 2009

Pulmonary Pharmacology & Therapeutics

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“…In addition, the anti-inflammatory potential of these compounds has also been demonstrated in animal models of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus [4,[7][8][9][10].…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, a potent anti-inflammatory effect of HDAC inhibitors at concentrations lower than those needed to suppress tumour cell growth in vitro and in vivo has been discovered [7]. This has proven to be advantageous in autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus, where treatment with HDAC inhibitors blocks production of inflammatory mediators such as nitric oxide (NO) and cytokines in vitro and disease progression in vivo in animal models [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells

et al. 2007

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Aims/hypothesis The immune-mediated elimination of pancreatic beta cells in type 1 diabetes involves release of cytotoxic cytokines such as IL-1β and IFNγ, which induce beta cell death in vitro by mechanisms that are both dependent and independent of nitric oxide (NO). Nuclear factor kappa B (NFκB) is a critical signalling molecule in inflammation and is required for expression of the gene encoding inducible NO synthase (iNOS) and of proapoptotic genes. NFκB has recently been shown to associate with chromatin-modifying enzymes histone acetyltransferases and histone deacetylases (HDAC), and positive effects of HDAC inhibition have been obtained in several inflammatory diseases. Thus, the aim of this study was to investigate whether HDAC inhibition protects beta cells against cytokine-induced toxicity. Materials and methods The beta cell line, INS-1, or intact rat islets were precultured with HDAC inhibitors suberoylanilide hydroxamic acid or trichostatin A in the absence or presence of IL-1β and IFNγ. Effects on insulin secretion and NO formation were measured by ELISA and Griess reagent, respectively. iNOS levels and NFκB activity were measured by immunoblotting and by immunoblotting combined with electrophoretic mobility shift assay, respectively. Viability was analysed by 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and apoptosis by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay and histone-DNA complex ELISA. Results HDAC inhibition reduced cytokine-mediated decrease in insulin secretion and increase in iNOS levels, NO formation and apoptosis. IL-1β induced a bi-phasic phosphorylation of inhibitor protein kappa Bα (IκBα) with the 2nd peak being sensitive to HDAC inhibition. No effect was seen on IκBα degradation and NFκB DNA binding. Conclusions/interpretation HDAC inhibition prevents cytokine-induced beta cell apoptosis and impaired beta cell function associated with a downregulation of NFκB transactivating activity.

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Histone Acetylation and Deacetylation

Kemp

Schroeder

Wagner

et al. 2012

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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

Cited by 473 publications

References 37 publications

Conserved responses to trichostatin A in rodent lungs exposed to endotoxin or stretch

Conserved responses to trichostatin A in rodent lungs exposed to endotoxin or stretch

Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells

Histone Acetylation and Deacetylation

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