Inhibitors of Histone Deacetylases as Antiinflammatory Drugs

C.A. Dinarello

3.1 Introduction 46

3.1.1 HDAC Inhibitors as Anti-tumor Agents 47

3.1.2 HDAC Inhibition and Expression of Latent Viral Genes 47

3.2 HDAC Inhibitors in Models of Inflammatory Diseases 48

3.2.1 Models of Lupus Erythematosus 48

3.2.2 Graft-Versus-Host Disease 50

3.2.3 Models of Arthritis 50

3.2.4 Hepatitis Induced by Intravenous Con A 51

3.3 Reducing Cytokines by HDAC Inhibitors 51

3.3.1 Low Concentrations of HDAC Inhibitors are Anti-inflammatory Whereas High Concentrations Are Needed for Anti-tumor Effects . 51

3.3.2 Effect of SAHA on Secretion of IL-1ß 52

3.3.3 Other Cytokines 53

3.3.4 LPS-Induced Cytokines In Vivo 54

3.4 Mechanism of Action of HDAC Inhibition in Reducing Inflammation 55

References 56

Abstract. This review addresses the issue of histone deacetylase (HDAC) inhibitors as developed for the treatment of cancer and for the investigation of the inhibition of inflammation. The review focuses on both in vitro and in vivo models of inflammation and autoimmunity. Of particular interest is the inhibi tion of pro-inflammatory cytokines. Although the reduction in cytokines appears paradoxical at first, upon examination, some genes that are anti-inflammatory are upregulated by inhibition of HDAC. Whether skin diseases will be affected by inhibitors of HDAC remains to be tested.

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