ReviewHistone deacetylase inhibitors: new drugs for the treatment of inflammatory diseases?
Section snippets
HDAC inhibitors
Mammalian HDACs have been classified into three classes [7, 17, 18]. Class I HDACs (HDACs 1, 2, 3 and 8) are homologues of yeast RPD3 and are found exclusively in the nucleus. Class II HDACs (HDACs 4, 5, 6, 7, 9 and 10), homologues of yeast Hda1, are found in both the nucleus and the cytoplasm. HDAC11 has properties of both class I and class II HDACs. Class III HDACs (Sirt1-Sirt7) are homologues of yeast Sir2 and form a structurally distinct class of NAD-dependent enzymes [7, 17, 18]. Northern
HDAC inhibitors, cytokine and NO expression and inflammatory diseases
Recent results have indicated that HDAC inhibitors can reduce the cytokine and NO production that contribute to various inflammatory diseases [15, 26, 27, 28]. Thus, the observation that butyrate and TSA inhibit IL-8 expression in colonic epithelial cells suggested that HDAC inhibitors can be used for the effective treatment of ulcerative colitis through increased histone acetylation and reduced production of pro-inflammatory cytokines by the intestinal epithelium (Table 1) [14, 15, 26].
HDAC inhibitors and transcription factors
Several results have demonstrated inhibition of NF-ĪŗB transcriptional activity after treatment with HDAC inhibitors. As initially reported, this transcription factor is crucial for the expression of numerous pro-inflammatory mediators, such as inducible NO synthase (iNOS), IL-6, IL-8, IL-10 and IL-12 [29, 34, 36]. Moreover, other anti-inflammatory drugs, such as salicylates and glucocorticoids, are also known to inhibit NF-ĪŗB [1]. However, and as discussed in a subsequent section, activation of
HDAC inhibitors, inflammation and cancer: an example of osteo-articular diseases
Here, osteo-articular tissue will be used as an example to discuss how inhibition of inflammation and bone resorption by HDAC inhibitors could help explain their anti-tumour activities. However, this hypothesis, which could be extended to other tissues and malignancies, needs additional evaluation in animal models and human clinical trials.
Primary or metastatic bone tumours favour inflammation and osteoclast-mediated bone resorption. The candidates for osteolytic mediators are vitamins (VitD3),
Contraindications in inflammatory diseases
In contrast to these anti-inflammatory effects, TSA and SAHA have been shown to strongly potentiate microglial inflammation. These HDAC inhibitors enhanced the LPS-induced expression of IL-6, TNF-Ī±, macrophage inflammatory protein-2 and NO in primary microglial cells as well as in neural co-cultures (Table 1) [50]. Therefore, histone acetylation could participate in the inflammatory response associated with a variety of neurodegenerative diseases, stroke and traumatic brain injuries. Whether
New HDAC inhibitors
Based on their various sub-cellular localization, intra-tissue variation and non-redundant activity, the different HDACs are certainly implicated in various specific cellular processes, such as proliferation, metabolism and differentiation. For example, class I HDACs are mainly nuclear enzymes, whereas class II HDACs localize either to the cell nucleus or to the cytoplasm, depending on their phosphorylation and subsequent binding of 14-3-3 proteins.
Moreover, class II HDACs display a
Conclusions and perspectives
Butyrate improves the efficacy of conventional anti-inflammatory treatments in refractory ulcerative colitis [31], therefore, future trials will certainly analyse association of salicylates, glucocorticoids and/or anti-cytokine immunotherapy with low dose HDAC inhibitors for the treatment for other inflammatory diseases. Whether the administration of HDAC inhibitors should be local or systemic will certainly depend on the nature of the inflammatory disease, on the extent of inflammation and its
Acknowledgements
We thank Kanji Mori for critical comments on this manuscript and acknowledge support from the RĆ©gion des Pays de Loire, the Association de Recherche sur le Cancer (ARC), INSERM (Contrat de Recherche StratĆ©gique nĀ°4CR06F), the MinistĆØre de la Recherche (ACI nĀ°TS/0220044) and the ComitĆ© des Pays de Loire de la Ligue Contre le Cancer, France.
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