Histone deacetylase inhibitor KBH-A42 inhibits cytokine production in RAW 264.7 macrophage cells and in vivo endotoxemia model

Choi, Yongseok; Park, Song‐Kyu; Kim, Hwan Mook; Kang, Jong Soon; Yoon, Yeo Dae; Han, Sang Bae; Han, Jeung Whan; Yang, Jaeseok; Han, Gyoonhee

doi:10.3858/emm.2008.40.5.574

Cited by 59 publications

(51 citation statements)

References 23 publications

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“…The available studies on epigenetic modifiers in several animal models have shown different results; i.e. effects of epigenetic modifiers varied from having no effect to being beneficial in attenuating inflammatory cytokines and chemokines as well as inflammatory injury to the airway, digestive tract and joints (Choi et al, 2008;Iwata et al, 2002;Rahman, 2002;Zhang et al, 2010). The variability in results might be because previous studies have focused on effects pre-treatment with HDAC inhibitors has, rather than studying their therapeutic potential.…”

Section: Discussionmentioning

confidence: 60%

“…A more recent KBH-A42 HDAC inhibitor has been recognized as an anti-inflammatory drug through its capability of reducing the production of TNFα and nitric oxide in LPS-induced macrophages. This study has also shown that the substantial antiinflammatory response of KBH-A42 is mediated through the phosphorylation of p38MAPK, but not through the activation of ERK1/2 or JNK (Choi et al, 2008).…”

Section: Introductionmentioning

confidence: 86%

“…Our data also show that treatment with Aza+TSA significantly reduced LPS-induced apoptosis of BMDMs and improved cell survival. Other studies have shown that macrophages actively participate in the production of proinflammatory and inflammatory factors in response to LPS stimulation (Choi et al, 2008;Iwata et al, 2002;Nicodeme et al, 2010;Rahman, 2002;Zhang et al, 2010), and a recent study has shown the use of synthetic histone mimics in abrogating the expression of key LPS-inducible cytokines and chemokines, and modulating innate immunological responses (Nicodeme et al, 2010). Our data suggest that combinatorial Aza+TSA therapy at nanomolar concentration is more efficacious than therapy with either drug alone in preventing the release of LPS-induced chemokines and cytokines from macrophages.…”

Section: Discussionmentioning

confidence: 99%

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Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury

Jayakumar

Samanta

Rajasingh

et al. 2015

Journal of Cell Science

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Acute lung injury (ALI) during sepsis is characterized by bilateral alveolar infiltrates, lung edema, and respiratory failure. Here, we examined the efficacy of DNA methyl transferase (DNMT) inhibitor Aza (5-Aza 2-deoxycytidine), histone deacetylase (HDAC) inhibitor TSA (Trichostatin A), and combination therapy (Aza+TSA) in protection of ALI. In LPS-induced mouse ALI, post-treatment with a single dose of Aza+TSA showed a substantial attenuation of adverse lung histopathological changes, and inflammations. Importantly, these protective effects were due to significant macrophage phenotypic changes observed in LPS-stimulated macrophages treated with Aza+TSA as compared with untreated LPS-induced macrophages or LPS-stimulated macrophages treated with either drug alone. Further, we observed significantly lower levels of pro-inflammatory molecules and higher levels of anti-inflammatory molecules in LPS-induced macrophages treated with Aza+TSA than in LPS-induced macrophages treated with either drug alone. The protection was ascribed to dual effects by an inhibition of MAPK-HuR-TNF and activation of STAT3-Bcl2 pathways. Combinatorial treatment with Aza+TSA reduces inflammation and promotes an anti-inflammatory M2 macrophage phenotype in ALI. This finding gives further evidence that the epigenetic treatment has a therapeutic potential for patients with sepsis.

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Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury

Jayakumar

Samanta

Rajasingh

et al. 2015

Journal of Cell Science

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“…Trichostatin A has been shown to enhance the LPS-induced expression of Cox-2, Cxcl2, and Lfit2 in bone marrow-derived macrophages (Aung et al, 2006). A new HDAC inhibitor KBH-A42 showed antiinflammatory properties in vitro via suppression of the production of TNFa and nitric oxide (NO) by dose-dependent increase in DNA binding with AP-1 and decrease in p38 phosphorylation in macrophages (Choi et al, 2008). In the present study, we found that knockdown of expression of miR-146a restored the levels of IL-6 in TSA ⁄ LPS-treated cells in macrophages from aged mice, suggesting that TSA diminishes the production of IL-6 in LPS-treated macrophages from aged mice by up-regulating miR-146a expression (Fig.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated expression of miR‐146a contributes to age‐related dysfunction of macrophages

Jiang¹,

Xiang²,

Wang

et al. 2011

Aging Cell

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SummaryAge-associated immune dysfunction, characterized by increased systemic levels of cytokines, manifests as an increased susceptibility to infections. Thus, understanding these negative regulators of the immune response has paved the way to delineating signaling pathways that impact immune senescence. In the present study, we found that miR-146a, which negatively regulated the expression of IL-1b and IL-6, was highly expressed in aged mice. However, there was a lack of response to the stimulation of lipopolysaccharide (LPS) and proinflammatory cytokines in macrophages of aged mice. As a result, the negative feedback regulation loop with miR-146a involving down-regulation of inflammation factors was interrupted in aged mice. Aberrant NF-jB binding to the miR-146a promoter was demonstrated to be associated with the abnormal expression of miR-146a in aged mice. The DNA methyltransferase inhibitor (5-aza-2-deoxycytidine) and the histone deacetylase inhibitor [trichostatin A (TSA)] both significantly up-regulated miR-146a transcriptional activation by altering the DNA-binding activity of NF-jB in macrophages isolated from aged mice, which suggests that DNA methylation and histone acetylation are involved in the suppression of age-dependent miR-146a expression. Additionally, high levels of histone deacetylase (HDACs) expressions contributed to the inhibition of miR-146a expression in LPS-stimulated macrophages from aged mice in vitro. While the suppression of HDACs activities by TSA could improve LPS-induced inflammatory responses owing to up-regulation of miR-146a expression in macrophages from aged mice. These data indicate that the dysregulated expression of miR-146a results in the age-associated dysfunction of macrophages, and miR-146a may be a good target for the treatment of age-related inflammatory diseases.

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“…The HDAC inhibitors were reported to promote apoptosis as well as modulation of the expression of various proinflammatory cytokines (49). Cytokine inhibition equally shown for the HDAC inhibitor KBH-A42 in RAW 264.7 cells is paralleled by a suppressed MAP kinase phosphorylation (50).…”

Section: Dendritic Cells and Macrophagesmentioning

confidence: 99%

Inhibition of Histone Deacetylases in Inflammatory Bowel Diseases

Glauben

Siegmund

2011

Mol Med

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This review, comprised of our own data and that of others, provides a summary overview of histone deacetylase (HDAC) inhibition on intestinal inflammation as well as inflammation-mediated carcinogenesis. Experimental colitis in mice represents an excellent in vivo model to define the specific cell populations and target tissues modulated by inhibitors of HDAC. Oral administration of either suberyolanilide hydroxamic acid (SAHA) or ITF2357 results in an amelioration in these models, as indicated by a significantly reduced colitis disease score and histological score. This effect was paralleled by suppression of proinflammatory cytokines at the site of inflammation as well as specific changes in the composition of cells within the lamina propria. In addition, tumor number and size was significantly reduced in two models of inflammation-driven tumorigenesis, namely interleukin (IL)-10-deficient mice and the azoxymethane-dextran sulfate sodium (DSS) model, respectively. The mechanisms affected by HDAC inhibition, contributing to this antiinflammatory and antiproliferative potency will be discussed in detail. Furthermore, with regard to the relevance in human inflammatory bowel disease, the doses of ITF2357 considered safe in humans and the corresponding serum concentrations are consistent with the efficacious dosing used in our in vivo as well as in vitro experiments. Thus, the data strongly suggest that HDAC inhibitors could serve as a therapeutic option in inflammatory bowel disease.

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Histone deacetylase inhibitor KBH-A42 inhibits cytokine production in RAW 264.7 macrophage cells and in vivo endotoxemia model

Cited by 59 publications

References 23 publications

Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury

Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury

Dysregulated expression of miR‐146a contributes to age‐related dysfunction of macrophages

Inhibition of Histone Deacetylases in Inflammatory Bowel Diseases

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