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The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance
Open accessAbstract
Antigen-presenting cells (APCs) induce T cell activation as well as T cell tolerance. The molecular basis of the regulation of this critical 'decision' is not well understood. Here we show that HDAC11, a member of the HDAC histone deacetylase family with no prior defined physiological function, negatively regulated expression of the gene encoding interleukin 10 (IL-10) in APCs. Overexpression of HDAC11 inhibited IL-10 expression and induced inflammatory APCs that were able to prime naive T cells and restore the responsiveness of tolerant CD4+ T cells. Conversely, disruption of HDAC11 in APCs led to upregulation of expression of the gene encoding IL-10 and impairment of antigen-specific T cell responses. Thus, HDAC11 represents a molecular target that influences immune activation versus immune tolerance, a critical 'decision' with substantial implications in autoimmunity, transplantation and cancer immunotherapy.
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TL;DR
HDAC11 is identified as a negative transcriptional regulator of IL-10 in antigen-presenting cells, acting mainly at the distal Il10 promoter and requiring its deacetylase activity. Manipulating HDAC11 changes APC inflammatory status and alters priming versus tolerance of antigen-specific CD4+ T cells.
Key findings
- Overexpression of HDAC11 inhibited LPS-induced IL-10 mRNA in RAW264.7 macrophages, primary mouse macrophages, human dendritic cells and THP-1 cells, while increasing IL-12 mRNA in several of these APC populations; HDAC11 knockdown or stable HDAC11-deficient RAW264.7 clones showed the opposite IL-10 effect.
- HDAC11 acted at the distal Il10 promoter: HDAC11 was detected mainly in the distal region (positions −807 to −1653), and adding this distal Il10 segment to the short Il12 promoter (−1 to −756) conferred strong HDAC11-mediated inhibition. HDAC11 was not detected on the Il12 promoter.
- Intact enzymatic activity was required: wild-type HDAC11 inhibited IL-10 mRNA, whereas an HDAC11 mutant lacking the deacetyltransferase domain failed to inhibit and instead increased IL-10 mRNA, suggesting dominant-negative action.
- Functionally, HDAC11-overexpressing macrophages expressed more CD86 and CD40, produced less IL-10 and more IL-12, activated naive hemagglutinin-specific CD4+ T cells more strongly, and restored IL-2 and IFN-γ production in tolerant CD4+ T cells; APCs lacking HDAC11 impaired antigen-specific CD4+ T cell responses.
Methods
- Used mouse RAW264.7 macrophages, primary mouse peritoneal macrophages, human THP-1 monocytic cells and human monocyte-derived dendritic cells; BALB/c mice and influenza hemagglutinin TCR-transgenic mice were used for T cell studies.
- Overexpressed Flag- and GFP-tagged HDAC4–HDAC11 via adenovirus, knocked down HDAC11 with lentiviral shRNA, and used Il10, Il12 and chimeric Il10-Il12 luciferase reporter assays, ChIP, real-time RT-PCR, immunoblot, ELISA and flow cytometry.
- mRNA was normalized to GAPDH with the Pfaffl method; assays were done in triplicate and repeated at least three times; T cell cytokine production was expressed as pg/ml per 1 × 10² clonotype-positive CD4+ T cells.
Limitations
- The paper does not state limitations.
- Evident from the text: most mechanistic work was done in transformed cell lines and in vitro primary APCs, with human data limited largely to mRNA measurements in dendritic cells and THP-1 cells.
- Evident from the text: HDAC11 was manipulated in APCs in vitro, while the tolerance model involved in vivo peptide-induced T cell tolerance; the proposed distal-to-proximal chromatin “scaffolding” mechanism is presented as plausible rather than directly demonstrated.
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78 Own result · 13 Own interpretation · 9 Not checked yet · 5 Own method · 4 No basis given
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In the paper
“Transduction of PEMs with short hairpin RNA (shRNA) specific for mouse HDAC11 resulted in higher expression of IL-10 mRNA in response to LPS stimulation relative to that of PEMs transduced with nontargeting shRNA (Fig. 2d).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Effects of HDAC11 overexpression in mouse and human APCs
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In the paper
“Similarly, we also noted less IL-10 mRNA and more IL-12 mRNA in primary human dendritic cells (Fig. 2b) and THP-1 human monocytic cells (Fig. 2c) overexpressing HDAC11.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Effects of HDAC11 overexpression in mouse and human APCs
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“only HDAC11 overexpression resulted in the inhibition of luciferase activity in response to LPS stimulation (Fig. 1b).”
- Also stated in: § HDAC 11 interacts with the Il10 promoter · boosted
“There was again strong inhibition of lucifease activity in LPS-stimulated cells transfected with the Il10 reporter gene and overexpressing HDAC11 (Fig. 3a).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Histone deacetylases and Il10 expression
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In the paper
“Infection of macrophages with adenovirus encoding HDAC4, HDAC5, HDAC7, HDAC8, HDAC9 or HDAC10 did not affect the ability of these cells to express IL-10 mRNA in response to LPS stimulation.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Histone deacetylases and Il10 expression
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“Overexpression of HDAC6 (A001723) in RAW264.7 cells, however, was associated with enhanced IL-10 mRNA expression in response to LPS (Fig. 1a).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Histone deacetylases and Il10 expression
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“overexpression of HDAC11 was associated with higher IL-12 mRNA expression in PEMs in response to LPS than that of PEMs infected with adenovirus vector encoding GFP (Fig. 2a).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Effects of HDAC11 overexpression in mouse and human APCs
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“PEMs infected with adenovirus encoding HDAC11 did not increase IL-10 mRNA expression in response to LPS (Fig. 2a).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Effects of HDAC11 overexpression in mouse and human APCs
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“we also noted less IL-10 mRNA and more IL-12 mRNA in primary human dendritic cells (Fig. 2b)”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Effects of HDAC11 overexpression in mouse and human APCs
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“we also noted less IL-10 mRNA and more IL-12 mRNA in primary human dendritic cells (Fig. 2b)”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Effects of HDAC11 overexpression in mouse and human APCs
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“Here we show that HDAC11, a member of the HDAC histone deacetylase family with no prior defined physiological function, negatively regulated expression of the gene encoding interleukin 10 (IL-10) in APCs.”
- Also stated in: § Abstract · plain
“Here we show that histone deacetylase 11 (HDAC11), by interacting with the distal segment of the promoter of the gene encoding IL-10 (Il10), negatively regulated the expression of this cytokine in mouse and human APCs.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > Abstract
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“stimulation of these two clones with LPS resulted in more IL-10 mRNA expression than that of cells transduced with nontargeting shRNA (Fig. 2e).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Effects of HDAC11 overexpression in mouse and human APCs
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“Similarly, we also noted less IL-10 mRNA and more IL-12 mRNA in primary human dendritic cells (Fig. 2b) and THP-1 human monocytic cells (Fig. 2c) overexpressing HDAC11.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Effects of HDAC11 overexpression in mouse and human APCs
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“Overexpression of HDAC11 resulted in blunted expression of IL-10 mRNA in LPS-treated RAW264.7 cells (Fig. 1a).”
- Also stated in: § Effects of HDAC11 overexpression in mouse and human APCs · plain
“Overexpression of wild-type HDAC11 inhibited IL-10 mRNA expression in LPS-treated RAW264.7 cells relative to that of cells transfected with empty vector (Fig. 2f).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Histone deacetylases and Il10 expression
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In the paper
“Inhibition of HDAC11 expression in PEMs did not affect IL-12 mRNA expression in response to LPS relative to that of control cells (Fig. 2d).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Effects of HDAC11 overexpression in mouse and human APCs
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“ChIP analysis of the acetylation status of histones H3 and H4 in LPS-stimulated control cells (infected with adenovirus expressing GFP) showed peak acetylation in the proximal region of the Il10 promoter by 60 min, followed by a rapid decrease (Fig. 4b,c).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
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“Overexpression of HDAC11 or GFP in RAW264.7 cells transfected with the ‘short region’ of the Il12 promoter resulted in similar luciferase activity in response to LPS stimulation (Fig. 3c).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > HDAC 11 interacts with the Il10 promoter
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“in macrophages overexpressing HDAC11, there was no acetylation of histones H3 and H4 in the proximal promoter at any time points evaluated (Fig. 4b,c).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
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“Instead, these cells had more IL-10 mRNA expression in response to LPS (Fig. 2f)”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Effects of HDAC11 overexpression in mouse and human APCs
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“the distal region of the Il10 promoter had only minimal changes in such phosphorylation in response to LPS in either control cells or cells overexpressing HDAC11 (Fig. 4a).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
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“We detected HDAC11 mainly on the distal region of the Il10 promoter (Fig. 3d).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > HDAC 11 interacts with the Il10 promoter
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“in control cells stimulated with LPS, there was such phosphorylation in the proximal region of the Il10 promoter, which reached its peak by 30 min and was followed by a progressive decrease (Fig. 4a).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
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“In response to LPS stimulation, there was a trend toward more IL-12 mRNA expression in RAW264.7 clones (Fig. 2e).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Effects of HDAC11 overexpression in mouse and human APCs
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“The absence of HDAC11 was associated with lower baseline expression of IL-12 mRNA in both clones relative to that of control cells (Fig. 2e).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Effects of HDAC11 overexpression in mouse and human APCs
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“overexpression of HDAC11 in RAW264.7 cells transfected with the Il10-Il12 chimeric promoter completely abrogated the increase in luciferase activity in response to LPS stimulation (Fig. 3c).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > HDAC 11 interacts with the Il10 promoter
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“in cells transfected with the Il12 reporter gene, overexpression of HDAC11 did not inhibit luciferase activity in response to LPS (Fig. 3a).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > HDAC 11 interacts with the Il10 promoter
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“Using a similar approach, we did not detect HDAC11 in the Il12 promoter region (Supplementary Fig. 3a online).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > HDAC 11 interacts with the Il10 promoter
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“There was no such inhibition, however, in RAW264.7 cells transfected with the enzymatically inactive mutant HDAC11.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Effects of HDAC11 overexpression in mouse and human APCs
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“there was no binding of STAT3 to the proximal promoter in macrophages overexpressing HDAC11 (Fig. 4f).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
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“macrophages overexpressing HDAC11 did not show such changes in response to LPS stimulation (Fig. 4e).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
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“It reached a peak by 60 min, followed by a progressive decrease (Fig. 4c).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
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“there was only a minimal and transient increase in the binding of RNA polymerase II in macrophages infected with adenovirus expressing HDAC11 (Fig. 4d).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
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“Again, we found no such changes in cells overexpressing HDAC11 (Fig. 4c).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
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“ChIP analysis of the proximal and distal segments of the Il12 promoter showed no inhibition in the acetylation of histones H3 and H4 in macrophages overexpressing HDAC11 (Supplementary Fig. 3b,c).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
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“in control macrophages, the changes in histone acetylation and binding of transcription factors to the proximal region of the Il10 promoter coincided temporally with maximum expression of IL-10 mRNA (60–120 min; Supplementary Fig. 4 online).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
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“PU.1 showed no changes to its binding in either control macrophages or in cells overexpressing HDAC11, by ChIP analysis of this region (Fig. 4g).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
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“Macrophages infected with adenovirus expressing GFP and stimulated with LPS had a rapid increase in the binding of RNA polymerase II, followed by a progressive decrease in the proximal but not in the distal region of the Il10 promoter (Fig. 4d).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
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“In the distal region of the Il10 promoter, there were only minimal changes in histone H3 acetylation in control cells or HDAC11-overexpressing cells (Fig. 4b).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
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“There were no substantial alterations in the abundance of Sp1 or STAT3 in the distal Il10 promoter region for either group of macrophages (Fig. 4e,f).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
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“After treatment with LPS, we detected more production of IL-10 and less production of IL-12 in cells lacking HDAC11 than in control wild-type cells or cells transfected with nontargeting shRNA (Fig. 6c).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Functional changes in APCs overexpressing or lacking HDAC11
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“cells lacking HDAC11 had more acetylation of histones H3 and H4 than did control cells in response to LPS (Fig. 5b,c).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter in cells lacking HDAC11
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“IL-12 production was higher in HDAC11-overexpressing PEMs than in control PEMs (Fig. 6b).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Functional changes in APCs overexpressing or lacking HDAC11
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“There were no such changes in the proximal Il10 promoter region (Fig. 4h).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
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“More notably, PEMs overexpressing HDAC11 were able to restore the responsiveness of tolerant CD4+ T cells.”
- Also stated in: § HDAC11 influences antigen-specific CD4+ T cell responses · plain
“In contrast, tolerant T cells encountering antigen on PEMs overexpressing HDAC11 regained their ability to produce IL-2 and IFN-γ (Fig. 7b).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > HDAC11 influences antigen-specific CD4+ T cell responses
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In the paper
“the transcription repressor PU.1 was minimally detected in the distal Il10 promoter of cells lacking HDAC11 relative to that of control cells (Fig. 5g).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter in cells lacking HDAC11
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“Kinetic analysis of the Il10-transcription activators Sp1 and STAT3 in cells lacking HDAC11 showed earlier and greater detection of both transcription factors in the proximal Il10 promoter relative to that of control cells (Fig. 5e,f).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter in cells lacking HDAC11
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“we found no differences in the kinetics of phosphorylation of Ser10 of histone H3 in the proximal Il10 promoter of cells with or without expression of HDAC11 (Fig. 5a).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter in cells lacking HDAC11
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“produced less IL-10 than did uninfected PEMs or PEMs infected with adenovirus expressing GFP alone (Fig. 6b).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Functional changes in APCs overexpressing or lacking HDAC11
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“Clonotypic T cells encountering hemagglutinin peptide on PEMs infected with HDAC11 were better activated, as they produced more IL-2 and interferon-γ (IFN-γ; Fig. 7a) than did clonotypic T cells recognizing antigen on uninfected PEMs or PEMs infected with adenovirus encoding GFP.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > HDAC11 influences antigen-specific CD4+ T cell responses
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“the transcriptional activity of the Il10 promoter, as determined by binding of RNA polymerase II to the proximal promoter, was of greater magnitude in cells lacking HDAC11 than in control cells stimulated with LPS (Fig. 5d).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter in cells lacking HDAC11
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“We did not detect IL-10 or IL-12 by enzyme-linked immunosorbent assay (ELISA) in the supernatants of these cells in the absence of LPS stimulation (data not shown).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Functional changes in APCs overexpressing or lacking HDAC11
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“Macrophages overexpressing HDAC11 had more expression of the costimulatory molecules CD86 and CD40 (Fig. 6a)”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Functional changes in APCs overexpressing or lacking HDAC11
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“When IL-10-neutralizing antibodies were added, there were no changes in the production of IL-12 in either PEMs overexpressing HDAC11 or control PEMs (Fig. 6d).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Functional changes in APCs overexpressing or lacking HDAC11
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“the distal segment of the Il10 promoter represented the common region in which we detected both HDAC11 (Fig. 3d) and PU.1 (Fig. 4g)”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
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“This higher IL-12 expression, however, was not different from the enhancement in IL-12 in control cells treated with IL-10-neutralizing antibodies (Fig. 6e).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Functional changes in APCs overexpressing or lacking HDAC11
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“There were again no substantial chromatin changes in the distal Il10 promoter of cells lacking HDAC11 (Fig. 5a–d).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter in cells lacking HDAC11
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“After the addition of IL-10-neutralizing antibodies, RAW264.7 clone 18 cells had higher IL-12 mRNA expression than did clone 18 cells cultured without antibody to IL10 (anti-IL-10; Fig. 6e).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Functional changes in APCs overexpressing or lacking HDAC11
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“After treatment with LPS, we detected more production of IL-10 and less production of IL-12 in cells lacking HDAC11 than in control wild-type cells or cells transfected with nontargeting shRNA (Fig. 6c).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Functional changes in APCs overexpressing or lacking HDAC11
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“First, we detected HDAC11 only in the distal region of the Il10 promoter.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
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“Similarly, T cells remained unresponsive to hemagglutinin peptide presented by PEMs infected with adenovirus encoding GFP (Fig. 7b).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > HDAC11 influences antigen-specific CD4+ T cell responses
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“Of note, detection of the transcription repressors PU.1 and HDAC11 in the distal promoter region was a late event that peaked at 2 h, perhaps as a counter-regulatory mechanism to diminish Il10 transcriptional activation.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
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“Perhaps the most convincing proof of the required interaction between HDAC11 and the distal Il10 promoter region was provided by experiments in which we found strong inhibition of gene expression by HDAC11 after adding only the distal segment of the Il10 promoter to the ‘short region’ of the Il12 promoter.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
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“Instead, there was more IL-10 mRNA expression, which was perhaps a result of the HDAC11 mutant’s acting as a dominant negative variant and therefore competing with endogenous HDAC11.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
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“Second, ChIP analysis of the proximal and distal Il10 promoter regions showed changes in HDAC11 mainly in the distal promoter region.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
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“In these cells, with early phosphorylation of histone H3 at Ser10 as the only exception, all of the subsequent events were substantially altered, which resulted in less binding of necessary transcription activators such as STAT3 or Sp1 to the proximal Il10 promoter region.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
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“That sequence of events ultimately led to transcriptional activation of Il10 that reached its peak by 2 h after LPS treatment.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
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“There was similar enhancement in Il10 expression in APCs lacking HDAC11.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
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In the paper
“In our studies, an early event after stimulation of macrophages with LPS was phosphorylation of Ser10 of histone H3 in the proximal Il10 promoter.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
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In the paper
“The enzymatic activity of HDAC11 seemed to be required for the process described above, as overexpression of a HDAC11 mutant with a deleted deacetyltransferase domain failed to inhibit Il10 expression.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
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In the paper
“IL-10 can serve a key function in tolerance induction by keeping immune responses in check and preventing self tissue damage13–15.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > Abstract
What the sources say
- Not checked yetcites [13] Moore, K.W., de Waal Malefyt, R., Coffman, R.L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001). source
- Not checked yetcites [14] Li, M.O. & Flavell, R.A. Contextual regulation of inflammation: a duet by transforming growth factor-β and interleukin-10. Immunity 28, 468–476 (2008). source
- Not checked yetcites [15] Rubtsov, Y.P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008). source
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In the paper
“there was less HDAC11 protein in cells transduced with a lentivirus encoding HDAC11-specific shRNA (Supplementary Fig. 1a online).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Effects of HDAC11 overexpression in mouse and human APCs
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In the paper
“which suggested that the HDAC11 mutant might be acting as a dominant negative variant.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Effects of HDAC11 overexpression in mouse and human APCs
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In the paper
“intact enzymatic deacetylase activity was required for HDAC11-mediated inhibition of Il10 expression in APCs.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Effects of HDAC11 overexpression in mouse and human APCs
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In the paper
“Our results collectively provide evidence that HDAC11 exerts its negative regulatory effect at the distal segment of the Il10 promoter.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > HDAC 11 interacts with the Il10 promoter
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In the paper
“Instead, it is likely that the changes in IL-12 expression were secondary to the effect of this HDAC on Il10 expression.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Functional changes in APCs overexpressing or lacking HDAC11
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In the paper
“by interacting with the distal segment of the promoter of the gene encoding IL-10 (Il10)”
- Also stated in: § HDAC 11 interacts with the Il10 promoter · plain
“We detected HDAC11 mainly on the distal region of the Il10 promoter (Fig. 3d).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > Abstract
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- Also stated in: § HDAC 11 interacts with the Il10 promoter · plain
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In the paper
“These results, together with our failure to detect HDAC11 in the Il12 promoter, suggest that HDAC11 did not directly influence Il12 expression in APCs.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Functional changes in APCs overexpressing or lacking HDAC11
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In the paper
“Thus, HDAC11 represents a molecular target that influences immune activation versus immune tolerance, a critical ‘decision’ with substantial implications in autoimmunity, transplantation and cancer immunotherapy.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > Abstract
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In the paper
“Several lines of evidence indicated that the distal Il10 promoter region is the target for HDAC11.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
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In the paper
“Studies with a T cell receptor–transgenic model have demonstrated that anti-hemagglutinin CD4+ transgenic T cells are rendered tolerant after in vivo exposure to high doses of hemagglutinin peptide29.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > HDAC11 influences antigen-specific CD4+ T cell responses
What the sources say
- Not checked yetcites [29] Cheng, F. et al. A critical role for Stat3 signaling in immune tolerance. Immunity 19, 425–436 (2003). source
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In the paper
“Conversely, disruption of this sequence of molecular events would negatively affect IL-10 production by the APC.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
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In the paper
“Here we have unambiguously identified HDAC11 as a negative transcriptional regulator of Il10 expression in mouse and human APCs.”
- Also stated in: § DISCUSSION · plain
“In summary, here we have identified a previously unknown function for HDAC11 as a transcriptional repressor of Il10 expression in APCs.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
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- Also stated in: § DISCUSSION · plain
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In the paper
“The additional demonstration that genetic manipulation of HDAC11 influenced the inflammatory status of APCs and their ability to determine the functional response of antigen-specific CD4+ T cells indicates that this molecule is a likely target for influencing APC-mediated immune activation versus immune tolerance.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
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- Rests on an assumption: The in vitro antigen-presentation assays with PEMs and RAW264.7 cells reflect the functional response of antigen-specific CD4+ T cells in vivo.
- It may state two separate claims as one. 19
- Probably not a substantial claim. 12
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In the paper
“In macrophages overexpressing HDAC11, we found a similar pattern of phosphorylation; the only difference was that after the peak at 30 min, there was a more rapid decrease in this phosphorylation (Fig. 4a).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In macrophages overexpressing HDAC11, binding of PU.1 to the distal promoter was already increased at time 0 and it increased further in response to LPS (Fig. 4g).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“ChIP analysis of the distal promoter region of control macrophages showed that PU.1 binding reached a peak within 2 h and remained increased for the duration of the analysis (Fig. 4g).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“binding of STAT3 to the proximal region of the Il10 promoter was evident within 60 min of LPS stimulation and reached its peak within 2 h in control macrophages (Fig. 4f)”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“HDAC11 was barely detected in the distal Il10 promoter of cells in which HDAC11 expression had been inhibited (Fig. 5h).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter in cells lacking HDAC11
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In control macrophages, changes in HDAC11 were detectable 2 h after LPS stimulation, were modest in magnitude and returned to baseline within 3 h (Fig. 4h).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Conversely, disruption of HDAC11 in APCs led to upregulation of expression of the gene encoding IL-10 and impairment of antigen-specific T cell responses.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In macrophages overexpressing HDAC11, there was more binding of this molecule at time 0; it reached its peak within 2 h of LPS stimulation and was followed by a rapid return to baseline within 3 h (Fig. 4h).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Overexpression of HDAC11 inhibited IL-10 expression and induced inflammatory APCs that were able to prime naive T cells and restore the responsiveness of tolerant CD4+ T cells.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Indeed, anti-hemagglutinin CD4+ T cells reisolated from these mice had minimal production of IL-2 and lacked IFN-γ production in response to restimulation with hemagglutinin peptide presented by uninfected control PEMs (Fig. 7b).”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > HDAC11 influences antigen-specific CD4+ T cell responses
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“This was followed by more acetylation of histones H3 and H4 and subsequent recruitment to the proximal promoter of the transcription factors Sp1 and STAT3.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Notably, although we detected HDAC11 mainly in the distal promoter region, most inhibitory effects on histone acetylation and recruitment of transcription factors occurred in the proximal region of the Il10 promoter.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In contrast to naive CD4+ T cells activated by APCs overexpressing HDAC11 (Fig. 7a), clonotypic CD4+ T cells encountering antigen in APCs lacking HDAC11 were functionally impaired, as they produced less IL-2 and lacked IFN-γ production (Fig. 7c) relative to the clonotypic T cells recognizing cognate antigen on wild-type RAW264.7 cells or RAW264.7 cells transduced with nontargeting shRNA.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > HDAC11 influences antigen-specific CD4+ T cell responses
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The additional demonstration that genetic manipulation of HDAC11 influenced the inflammatory status of APCs and their ability to determine the functional response of antigen-specific CD4+ T cells indicates that this molecule is a likely target for influencing APC-mediated immune activation versus immune tolerance.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“HDAC11 is a newly identified member of the HDAC family and thus far no known physiological function for HDAC11 has been demonstrated23.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Histone deacetylases and Il10 expression
What the sources say
- Not checked yetcites [23] Gao, L., Cueto, M.A., Asselbergs, F. & Atadja, P. Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J. Biol. Chem. 277, 25748–25755 (2002). source
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Published studies have shown that phosphorylation of histone H3 at the serine residue at position 10 (Ser10) is needed for transcriptional activation of the Il10 promoter24.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
What the sources say
- Not checked yetcites [24] Lucas, M., Zhang, X., Prasanna, V. & Mosser, D.M. ERK activation following macrophage FcγR ligation leads to chromatin modifications at the IL-10 locus. J. Immunol. 175, 469–477 (2005). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“PU.1 is a transcription repressor that interacts with the Il10 promoter27,28.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
What the sources say
- Not checked yetcites [27] Reuss, E. et al. Differential regulation of interleukin-10 production by genetic and environmental factors - a twin study. Genes Immun. 3, 407–413 (2002). source
- Not checked yetcites [28] Suzuki, M., Yamada, T., Kihara-Negishi, F., Sakurai, T. & Oikawa, T. Direct association between PU.1 and MeCP2 that recruits mSin3A-HDAC complex for PU.1-mediated transcriptional repression. Oncogene 22, 8688–8698 (2003). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“transcription factors known to interact with the Il10 promoter25,26.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > Changes in the Il10 promoter induced by HDAC11
What the sources say
- Not checked yetcites [25] Benkhart, E.M., Siedlar, M., Wedel, A., Werner, T. & Ziegler-Heitbrock, H.W. Role of Stat3 in lipopolysaccharide-induced IL-10 gene expression. J. Immunol. 165, 1612–1617 (2000). source
- Not checked yetcites [26] Tone, M., Powell, M.J., Tone, Y., Thompson, S.A.J. & Waldmann, H. IL-10 gene expression is controlled by the transcription factors Sp1 and Sp3. J. Immunol. 165, 286–291 (2000). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Such an effect not only determined the inflammatory status of these cells but also influenced priming versus tolerance of antigen-specific CD4+ T cells.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Dynamic changes in the chromatin structure of the Il10 promoter in T cells differentiated into the TH1 or TH2 phenotype closely regulate IL-10 expression32.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
What the sources say
- Not checked yetcites [32] Im, S.-H., Hueber, A., Monticelli, S., Kang, K.-H. & Rao, A. Chromatin-level regulation of the IL10 gene in T cells. J. Biol. Chem. 279, 46818–46825 (2004). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All real-time RT-PCR experiments were repeated at least three times with similar results.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > METHODS > Real-time RT-PCR
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In support of that possibility, studies have shown that conformational chromatin changes can regulate the transcription of several genes31.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
What the sources say
- Not checked yetcites [31] West, A.G. & Fraser, P. Remote control of gene transcription. Hum. Mol. Genet. 14, R101–R111 (2005). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Similarly, in macrophages, more acetylation of the Il10 promoter has been associated with enhanced transcription activity17.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > DISCUSSION
What the sources say
- Not checked yetcites [17] Zhang, X., Edwards, J.P. & Mosser, D.M. Dynamic and transient remodeling of the macrophage IL-10 promoter during transcription. J. Immunol. 177, 1282–1288 (2006). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data collectively indicate that whereas overexpression of HDAC11 in APCs effectively activated naive antigen-specific CD4+ T cells and restored the responsiveness of tolerant T cells, APCs devoid of HDAC11 induced the opposite effect, resulting in impairment of antigen-specific CD4+ T cell responses.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > RESULTS > HDAC11 influences antigen-specific CD4+ T cell responses
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All assays were done in triplicate and protein expression was evaluated by immunoblot analysis.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > METHODS > Adenovirus and lentivirus infection, transient transfection and luciferase reporter assays
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Cells were infected in conditions and with titrations to minimize cellular death and to obtain at least 70–90% of the cell population expressing the protein of interest.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > METHODS > Adenovirus and lentivirus infection, transient transfection and luciferase reporter assays
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The shRNA specific for HDAC11 was a combination of five sequences targeting different segments of HDAC11 mRNA. The nontargeting control shRNA was a single random sequence not present in the human or mouse genome.”
§ The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance > METHODS > Adenovirus and lentivirus infection, transient transfection and luciferase reporter assays
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
IL-10 negatively regulates IL-12 expression.
“Given that IL-10 negatively regulates IL-12 expression, the presence of IL-10 in our experimental system might have masked a potential direct regulatory effect of HDAC11 on Il12 expression.”
The paper relies on this without support.
The in vitro antigen-presentation assays with PEMs and RAW264.7 cells reflect the functional response of antigen-specific CD4+ T cells in vivo.
“The additional demonstration that genetic manipulation of HDAC11 influenced the inflammatory status of APCs and their ability to determine the functional response of antigen-specific CD4+ T cells indicates that this molecule is a likely target for influencing APC-mediated immune activation versus immune tolerance.”
The paper relies on this without support.
The molecules involved and the sequence of events mediating chromatin modifications of the Il10 promoter are not fully understood.
“However, the molecules involved and the sequence of events mediating these chromatin modifications are not fully understood.”
The paper relies on this without support.
Little is known about the function of HDAC11 in normal and/or transformed cells.
“Although there is much information about its structure, enzymatic activity and tissue distribution23,30, little is known about the function of this HDAC in normal and/or transformed cells.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Histone deacetylase 11 has been implicated in immune response cascades and shown to regulate the expression of the anti-inflammatory cytokine interleukin 10 (IL-10) by association with HDAC6 (Villagra et al., 2009).”
From Histone deacetylase 11 is an ε-N-Myristoyllysine hydrolase (2018) · cites this paper as Villagra et al., 2009
In the citing paper
“HDACs have been implicated in diverse biology including metabolism, inflammation, circadian rhythm, as well as neurological development and brain function (Guan et al., 2009; Villagra et al., 2009; Gräff et al., 2012; Jakovcevski and Akbarian, 2012; Falkenberg and Johnstone, 2014; Tough et al., 2016).”
From Histone deacetylase 11 is an ε-N-Myristoyllysine hydrolase (2018) · cites this paper as Villagra et al., 2009
In the citing paper
“It has been known for several years that HDAC11 negatively controls IL-10 transcriptional activity in antigen-presenting cells and regulates immune tolerance (Villagra et al., 2009).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Villagra et al., 2009
In the citing paper
“It has been known for several years that HDAC11 negatively controls IL-10 transcriptional activity in antigen-presenting cells and regulates immune tolerance (Villagra et al., 2009).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Villagra et al., 2009
Citations
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The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men
Yang, X., & Seto, E. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2346 · Cited by 1,277
Self-citation
Cited by
Sorted by citations
Kettenmann, H., Hanisch, U.-K., Noda, M., & Verkhratsky, A. (2011) · Physiological Reviews · doi:10.1152/physrev.00011.2010 · Cited by 3,547
The regulation of IL-10 production by immune cells
Saraiva, M., & O’Garra, A. (2010) · Nature reviews. Immunology · doi:10.1038/nri2711 · Cited by 3,293
The role of short chain fatty acids in health and disease
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Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders
Falkenberg, K. J., & Johnstone, R. W. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4360 · Cited by 1,564
The world of protein acetylation
Drazic, A., Myklebust, L. M., Ree, R., & Arnesen, T. (2016) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2016.06.007 · Cited by 847
Metadata
- Authors
- Villagra, A., Cheng, F., Wang, H.-W., Suarez, I., Glozak, M., Maurin, M., Nguyen, D., Wright, K. L., Atadja, P. W., Bhalla, K., Pinilla-Ibarz, J., Seto, E., & Sotomayor, E. M.
- Affiliations
- Moffitt Cancer Center (US)
- University of South Florida (US)
- Augusta University (US)
- Corresponding author
- Villagra, Alejandro
- Sotomayor, Eduardo M
- ORCID
- Venue
- Nature Immunology
- Published
- 2008-11-16
- Volume
- 10
- Issue
- 1
- Pages
- 92-100
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC3925685
- OpenAlex
- W1985845937
- Cited by
- 455
- References
- 39
- Citations by year
- 2026: 21 · 2025: 25 · 2024: 18 · 2023: 17 · 2022: 23 · 2021: 24 · 2020: 30 · 2019: 27 · 2018: 29 · 2017: 28 · 2016: 30 · 2015: 25 · 2014: 23 · 2013: 25 · 2012: 31
- FWCI
- 10.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5k08ca078656-03)
- National Cancer Institute (R01CA087583, CA78656, R01CA134807, R01CA100850, CA87583)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- HDAC11, histone deacetylase, IL-10, immune tolerance, antigen-presenting cells, T cell activation, T cell tolerance, inflammation, gene expression regulation, autoimmunity, transplantation, cancer immunotherapy
- MeSH terms
- Animals, Antigen-Presenting Cells, Cell Line, Gene Expression Regulation, Histone Deacetylases, Humans, Immune Tolerance, Lymphocyte Activation, Male, Mice, Inbred BALB C, CD4-Positive T-Lymphocytes, Down-Regulation, Interleukin-10, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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