Divergent roles of histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) on the transcriptional regulation of IL10 in antigen presenting cells

Cheng, Fengdong; Lienlaf, Maritza; Perez-Villarroel, Patricio; Wang, Hong Wei; Lee, Calvin; Woan, Karrune; Woods, David M.; Knox, Tessa; Bergman, Joel; Pinilla‐Ibarz, Javier; Kozikowski, Alan P.; Seto, Edward; Sotomayor, Eduardo M.; Villagra, Alejandro

doi:10.1016/j.molimm.2014.02.019

Cited by 121 publications

(86 citation statements)

References 31 publications

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“…More recently, Youn et al have revealed yet another HDAC—HDAC2 that is involved in silencing of the Rb1 MDSCs(Youn, Kumar et al 2013) which reiterates the importance of investigating these epigenetic factors in the context of MDSC biology. There is also new evidence that HDAC6 and HDAC11 proteins physically interact and are being recruited to the IL-10 gene promoter dictating dynamic transcriptional responses(Cheng, Lienlaf et al 2014). …”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase 11: A novel epigenetic regulator of myeloid derived suppressor cell expansion and function

Sahakian

Powers

Chen

et al. 2015

Molecular Immunology

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110

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Myeloid-derived suppressor cells (MDSC's), a heterogeneous population of cells capable of suppressing anti-tumor T cell function in the tumor microenvironment, represent an imposing obstacle in the development of cancer immunotherapeutics. Thus, identifying elements essential to the development and perpetuation of these cells will undoubtedly improve our ability to circumvent their suppressive impact. HDAC11 has emerged as a key regulator of IL-10 gene expression in myeloid cells, suggesting that this may represent an important targetable axis through which to dampen MDSC formation. Using a murine transgenic reporter model system where eGFP expression is controlled by the HDAC11 promoter (Tg-HDAC11-eGFP), we provide evidence that HDAC11 appears to function as a negative regulator of MDSC expansion/function in vivo. MDSCs isolated from EL4 tumor-bearing Tg-HDAC11-eGFP display high expression of eGFP, indicative of HDAC11 transcriptional activation at steady state. In striking contrast, immature myeloid cells in tumor-bearing mice display a diminished eGFP expression, implying that the transition of IMC to MDSC's require a decrease in the expression of HDAC11, where we postulate that it acts as a gate-keeper of myeloid differentiation. Indeed, tumor-bearing HDAC11-knockout mice (HDAC11-KO) demonstrate a more suppressive MDSC population as compared to wild-type (WT) tumor-bearing control. Notably, the HDAC11-KO tumor-bearing mice exhibit enhanced tumor growth kinetics when compare to the WT control mice. Thus, through a better understanding of this previously unknown role of HDAC11 in MDSC expansion and function, rational development of targeted epigenetic modifiers may allow us to thwart a powerful barrier to efficacious immunotherapies.

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Section: Discussionmentioning

confidence: 99%

Histone deacetylase 11: A novel epigenetic regulator of myeloid derived suppressor cell expansion and function

Sahakian

Powers

Chen

et al. 2015

Molecular Immunology

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110

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“…Accumulating evidence also indicates that HDAC6 is present in the nucleus(14, 15) where it can function as cofactor of specific transcription factors to influence gene promoter activity (14, 15, 18-20). Of note, HDAC6 has been also found to regulate inflammatory and immune responses (21-24).…”

Section: Discussionmentioning

confidence: 99%

“…In the cytoplasm, HDAC6 is recognized as a key regulator of cytoskeleton, cell migration and cell-cell interactions(16) given its effect upon the acetylation status of α-tubulin, Hsp90, and cortactin(17). In the nucleus, HDAC6 has been implicated in the regulation of specific transcription factors and gene promoters(14, 15, 18-20). Importantly, accumulating evidence also points to HDAC6 as playing an important role in regulation of inflammatory and immune responses, in particular at the level of the APC/T-cell immune synapse(21), regulatory T-cell function(22), macrophage responses(23) and aberrant airway inflammation (24).…”

Section: Introductionmentioning

confidence: 99%

A Novel Role for Histone Deacetylase 6 in the Regulation of the Tolerogenic STAT3/IL-10 Pathway in APCs

Cheng

Lienlaf

Wang

et al. 2014

The Journal of Immunology

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Antigen-presenting cells (APCs) are critical in T-cell activation and in the induction of T-cell tolerance. Epigenetic modifications of specific genes in the APC play a key role in this process, and among them, histone deacetylases (HDACs) have emerged as key participants. HDAC6, one of the members of this family of enzymes, has been shown to be involved in regulation of inflammatory and immune responses. Here we show for the first time, that genetic or pharmacologic disruption of HDAC6 in macrophages and dendritic cells resulted in diminished production of the immunosuppressive cytokine IL-10, and induction of inflammatory APCs that effectively activate antigen-specific naïve T-cells and restore the responsiveness of anergic CD4+ T-cells. Mechanistically, we have found that HDAC6 forms a previously unknown molecular complex with STAT3, association that was detected in both the cytoplasmic and nuclear compartments of the APC. By using HDAC6 recombinant mutants we identified the domain comprising aminoacids 503-840 as being required for HDAC6 interaction with STAT3. Furthermore, by re-chromatin immunoprecipitation we confirmed that HDAC6 and STAT3 are both recruited to the same DNA sequence within the Il10 gene promoter. Of note, disruption of this complex by knocking down HDAC6 resulted in decreased STAT3 phosphorylation -but no changes in STAT3 acetylation- as well as diminished recruitment of STAT3 to the Il10 gene promoter region. The additional demonstration that a selective HDAC6 inhibitor disrupts this STAT3/IL-10 tolerogenic axis points to HDAC6 as a novel molecular target in APCs to overcome immune tolerance and tips the balance towards T-cell immunity.

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“…Different classes of HDACs have distinct activities on histones H2A, H2B, H3, and H4 21. HDAC7 is proinflammatory and stimulates IL-6 expression,22 whereas HDAC6 and HDAC11 suppress anti-inflammatory cytokine, IL-10, expression in antigen-presenting cells 23. In contrast, HDAC2 and HDAC3 are anti-inflammatory and suppress proinflammatory cytokine gene expression.…”

Section: Discussionmentioning

confidence: 99%

Curcumin modulates the effect of histone modification on the expression of chemokines by type II alveolar epithelial cells in a rat COPD model

Gan¹,

Li²,

Wang³

et al. 2016

COPD

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BackgroundStudies have suggested that histone modification has a positive impact on various aspects associated with the progression of COPD. Histone deacetylase 2 (HDAC2) suppresses proinflammatory gene expression through deacetylation of core histones.ObjectiveTo investigate the effect of histone modification on the expression of chemokines in type II alveolar epithelial cells (AEC II) in a rat COPD model and regulation of HDAC2 expression by curcumin in comparison with corticosteroid.Materials and methodsThe rat COPD model was established by cigarette smoke exposure and confirmed by histology and pathophysioloy. AEC II were isolated and cultured in vitro from the COPD models and control animals. The cells were treated with curcumin, corticosteroid, or trichostatin A, and messenger RNA (mRNA) expression of interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2α (MIP-2α) was assessed by quantitative real-time polymerase chain reaction (RT-PCR). The expression of HDAC2 was measured by Western blot. Chromatin immunoprecipitation was used to detect H3/H4 acetylation and H3K9 methylation in the promoter region of three kinds of chemokine genes (IL-8, MCP-1, and MIP-2α).ResultsCompared to the control group, the mRNAs of MCP-1, IL-8, and MIP-2α were upregulated 4.48-fold, 3.14-fold, and 2.83-fold, respectively, in the AEC II from COPD model. The protein expression of HDAC2 in the AEC II from COPD model was significantly lower than from the control group (P<0.05). The decreased expression of HDAC2 was negatively correlated with the increased expression of IL-8, MCP-1, and MIP-2α mRNAs (all P<0.05). The level of H3/H4 acetylation was higher but H3K9 methylation in the promoter region of chemokine genes was lower in the cells from COPD model than from the control group (all P<0.05). Curcumin downregulated the expression of MCP-1, IL-8, and MIP-2α, and the expression was further enhanced in the presence of corticosteroid. Moreover, curcumin restored HDAC2 expression, decreased the levels of H3/H4 acetylation, and increased H3K9 methylation in the promoter region of chemokine in the presence or absence of dexamethasone (all P<0.05).ConclusionCurcumin may suppress chemokines and restore corticosteroid resistance in COPD through modulating HDAC2 expression and its effect on histone modification.

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Divergent roles of histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) on the transcriptional regulation of IL10 in antigen presenting cells

Cited by 121 publications

References 31 publications

Histone deacetylase 11: A novel epigenetic regulator of myeloid derived suppressor cell expansion and function

Histone deacetylase 11: A novel epigenetic regulator of myeloid derived suppressor cell expansion and function

A Novel Role for Histone Deacetylase 6 in the Regulation of the Tolerogenic STAT3/IL-10 Pathway in APCs

Curcumin modulates the effect of histone modification on the expression of chemokines by type II alveolar epithelial cells in a rat COPD model

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