Apicidin, the Histone Deacetylase Inhibitor, Suppresses TH1 Polarization of Murine Bone Marrow-Derived Dendritic Cells

Id, Jung; Lee, Jae Sung; Yi, Jeong; Cm, Lee; Jh, Chang; Sk, Jeong; Sh, Chun; Park, WS; Han, Jin; Shin, Young Kee; Park, Y-M

doi:10.1177/039463200902200227

Cited by 26 publications

(16 citation statements)

References 29 publications

(36 reference statements)

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“…Thus, we consider that HDAi alter dendritic cells to a tolerogenic-like phenotype. Some previous reports have reported that histone deacetylase (HDAC) inhibition alters dendritic cell function when lipopolysaccharide was used to stimulate and differentiate dendritic cells [34]. We have found similar results using ZyA, which signals through Dectin-1 and TLR-2, instead of lipopolysaccharide, which utilizes TLR-4, illustrating that HDAC inhibition alters dendritic cell function regardless of the stimulation.…”

Section: Discussionsupporting

confidence: 82%

Histone deacetylase inhibition alters dendritic cells to assume a tolerogenic phenotype and ameliorates arthritis in SKG mice

et al. 2011

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IntroductionThe purpose of this study was to elucidate the effects of histone deacetylase inhibition on the phenotype and function of dendritic cells and on arthritis in SKG mice.MethodsArthritis was induced in SKG mice by zymosan A injection. Trichostatin A, a histone deacetylase inhibitor, was administered and its effects on arthritis were evaluated by joint swelling and histological evaluation. Interleukin-17 production in lymph node cells was determined by an enzyme-linked immunosorbent assay (ELISA). Foxp3 expression in lymph node cells and the phenotypes of splenic dendritic cells were examined by fluorescence-activated cell sorting (FACS). Bone marrow-derived dendritic cells (BM-DC) were generated with granulocyte macrophage colony-stimulating factor. The effects of trichostatin A on cell surface molecules, cytokine production, indoleamine 2,3-dioxygenase (IDO) expression and T cell stimulatory capacity were examined by FACS, ELISA, quantitative real-time polymerase chain reaction and Western blot, and the allo-mixed lymphocyte reaction, respectively.ResultsTrichostatin A, when administered before the onset of arthritis, prevented SKG mice from getting arthritis. Trichostatin A treatment also showed therapeutic effects on arthritis in SKG mice, when it was administered after the onset of arthritis. Trichostatin A treatment reduced Th17 cells and induced regulatory T cells in lymph node, and also decreased co-stimulatory molecule expression on splenic dendritic cells in vivo. In vitro, trichostatin A markedly suppressed zymosan A-induced interleukin-12 and interleukin-6 production by BM-DC and up-regulated IDO expression at mRNA and protein levels. Trichostatin A-treated BM-DC also showed less T cell stimulatory capacity.ConclusionsHistone deacetylase inhibition changes dendritic cells to a tolerogenic phenotype and ameliorates arthritis in SKG mice.

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Section: Discussionsupporting

confidence: 82%

Histone deacetylase inhibition alters dendritic cells to assume a tolerogenic phenotype and ameliorates arthritis in SKG mice

et al. 2011

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“…The authors report that LAQ824 also inhibits DC and macrophage chemotaxis without altering that of neutrophils. As a whole, this study is in keeping with that of Jung et al showing that the HDACi apicidin suppresses DC-dependent Th1 polarization (34). Several reports, therefore, confirm that HDACi impairs DC functions and the ensuing T-cell proliferation remarkably through mechanisms related to modulation of specific gene expression, and not because of an overall deregulation of gene transcription.…”

Section: Possible Mechanisms Underlying the Therapeutic Effects Of Hdsupporting

confidence: 91%

The Therapeutic Potential of HDAC Inhibitors in the Treatment of Multiple Sclerosis

Faraco

Cavone

Chiarugi

2011

Mol Med

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Multiple sclerosis (MS) is a devastating autoimmune disorder of the central nervous system (CNS) for which there is no efficacious cure. Thanks to numerous preclinical and clinical studies, drugs able to mitigate the inexorable course of the disease have been made available recently. Still, there is a terrible need for compounds capable of reducing the severity of the autoimmune attack and of blocking progression of the disorder. Also, besides the classic immunosuppressive strategies, it is now appreciated that compounds directly targeting neuronal death can be of relevance to the treatment of MS patients. Acetylation homeostasis is a key regulator of both immune cell activation and neuronal survival. Of note, potent histone deacetylase inhibitors (HDACi) endowed with antiinflammatory and neuroprotective properties have been identified. Efficacy of HDACi in experimental models of MS has been reported consistently. In this review, we provide an appraisal of the literature on HDACi and MS, also discussing the mechanisms by which HDACi can suppress the autoimmune attack to the CNS.

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“…Reviewed in (74) Reduced disease severity in dextran sodium sulfate and trinitrobenzene sulfonic acid (TNBS) colitis (143,144) Decreased cytokine levels in colitis model (143,144) Reduced severity of colitis in HDAC-9-deficient mice (145) Suppression of COX-2 activation in colon cells (146) Immunosuppressive properties Reviewed in (43,75,76) Survival benefit in GvHD (71,72,147) Sparing effect on graft versus leukemia (71) Increased Foxp3 + T-regulatory cells (148,149) Reduced incidence of diabetes in NOD mouse (36) Induction of antigen-specific anergy in lymphocytes (150) Improved allograft transplantation (148,151) Induction of IDO and inhibition of dendritic cell maturation (44) Reduced nephritis in lupus-prone mice (119,120) Decrease disease severity in experimental allergic encephalitis (76,152) Suppression of Th1 polarization of murine dendritic cells (153) Inhibition of IL-2 gene expression in T cells (154,155) Reduced cytokine production in primary human T cells stimulated with anti-CD3/CD28 (156) Inhibition of CD154 (CD40L) expression in T cells (157) Models of arthritis Reviewed in (25,26) Reduced joint destruction in collagen-induced arthritis (25,158,159) Decreased bone and cartilage loss (25) Lower cytokine and chemokine levels (23,24) Decreased synovial cell proliferation (160) Abrogation of TGFβ-1-induced fibroblast-myofibroblast differentiation (161) Inhibition of IL-1β-induced matrix metalloproteinase expression in human articular chondrocytes (162)…”

Section: Models Of Inflammatory Bowel Diseasementioning

confidence: 99%

Histone Deacetylase Inhibitors for Treating a Spectrum of Diseases Not Related to Cancer

Dinarello

Fossati

Mascagni

2011

Mol Med

137

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This issue of Molecular Medicine contains 14 original research reports and state-of-the-art reviews on histone deacetylase inhibitors (HDACi's), which are being studied in models of a broad range of diseases not related to the proapoptotic properties used to treat cancer. The spectrum of these diseases responsive to HDACi's is for the most part due to several antiinflammatory properties, often observed in vitro but importantly also in animal models. One unifying property is a reduction in cytokine production as well as inhibition of cytokine postreceptor signaling. Distinct from their use in cancer, the reduction in inflammation by HDACi's is consistently observed at low concentrations compared with the higher concentrations required for killing tumor cells. This characteristic makes HDACi's attractive candidates for treating chronic diseases, since low doses are well tolerated. For example, low oral doses of the HDACi givinostat have been used in children to reduce arthritis and are well tolerated. In addition to the antiinflammatory properties, HDACi's have shown promise in models of neurodegenerative disorders, and HDACi's also hold promise to drive HIV-1 out of latently infected cells. No one molecular mechanism accounts for the non-cancer-related properties of HDACi's, since there are 18 genes coding for histone deacetylases. Rather, there are mechanisms unique for the pathological process of specific cell types. In this overview, we summarize the preclinical data on HDACi's for therapy in a wide spectrum of diseases unrelated to the treatment of cancer. The data suggest the use of HDACi's in treating autoimmune as well as chronic inflammatory diseases.

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Apicidin, the Histone Deacetylase Inhibitor, Suppresses TH1 Polarization of Murine Bone Marrow-Derived Dendritic Cells

Cited by 26 publications

References 29 publications

Histone deacetylase inhibition alters dendritic cells to assume a tolerogenic phenotype and ameliorates arthritis in SKG mice

Histone deacetylase inhibition alters dendritic cells to assume a tolerogenic phenotype and ameliorates arthritis in SKG mice

The Therapeutic Potential of HDAC Inhibitors in the Treatment of Multiple Sclerosis

Histone Deacetylase Inhibitors for Treating a Spectrum of Diseases Not Related to Cancer

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