Histone Deacetylase Inhibitor LAQ824 Augments Inflammatory Responses in Macrophages through Transcriptional Regulation of IL-10

Wang, Hongwei; Cheng, Fengdong; Woan, Karrune; Sahakian, Eva; Merino, Oscar; Rock-Klotz, Jennifer; Vicente-Suarez, Ildefonso; Pinilla‐Ibarz, Javier; Wright, Kenneth L.; Seto, Edward; Bhalla, Kapil N.; Villagra, Alejandro; Sotomayor, Eduardo M.

doi:10.4049/jimmunol.1001101

Cited by 45 publications

(39 citation statements)

References 51 publications

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“…Thus, low, nonapoptotic concentrations of the HDAC inhibitor ITF2357 reduce proinflammatory cytokine production in primary cells in vitro and exhibit antiinflammatory effects in vivo. In contrast, treatment of murine macrophages with the histone deacetylase inhibitor LAQ824 induced chromatin changes in the IL-10 gene promoter that results in recruitment of the transcriptional repressor HDAC11 (21). This result diminishes IL-10 production and induction of inflammatory cells.…”

Section: Continuedmentioning

confidence: 96%

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

Dinarello

Fossati

Mascagni

2011

Mol Med

138

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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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Section: Continuedmentioning

confidence: 96%

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

Dinarello

Fossati

Mascagni

2011

Mol Med

138

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“…Several US Food and Drug Administration (FDA)-approved small-molecule compounds inhibit the MERTK pathway although they were not originally developed for this purpose 190 . Myeloid cell functions are also regulated at the epigenetic level; as an example, drugs that interfere with chromatin remodelling, such as bromodomain and extra-terminal motif proteins 191,192 , or histone deacetylase (HDAC) inhibitors 193,194 , can affect inflammatory macro phage phenotypes. Other approaches to the modulation of macrophage functions include local low-dose ionizing radiation 146 and CD40 targeting, which can trigger macrophages to kill tumour cells 195 .…”

Section: Targeting Myeloid Cells To Limit Cancermentioning

confidence: 99%

The role of myeloid cells in cancer therapies

2016

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Recent clinical trials have demonstrated the ability to durably control cancer in some patients by manipulating T lymphocytes. These immunotherapies are revolutionizing cancer treatment but benefit only a minority of patients. It is thus a crucial time for clinicians, cancer scientists and immunologists to determine the next steps in shifting cancer treatment towards better cancer control. This Review describes recent advances in our understanding of tumour-associated myeloid cells. These cells remain less studied than T lymphocytes but have attracted particular attention because their presence in tumours is often linked to altered patient survival. Also, experimental studies indicate that myeloid cells modulate key cancer-associated activities, including immune evasion, and affect virtually all types of cancer therapy. Consequently, targeting myeloid cells could overcome limitations of current treatment options.

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“…Recently, we found that treatment of APCs with the pan-HDACi LAQ824 or LBH589 inhibits the production of the anti-inflammatory cytokine IL-10. This effect enabled the APCs to effectively prime naïve antigen-specific CD4 + T-cells and restore the responsiveness of tolerant T-cells isolated from tumor-bearing mice (28). These findings suggest that specific HDAC(s) likely participate in regulation of Il10 gene transcription and could be putative target(s) in the observed HDACi-mediated IL-10 inhibition.…”

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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Histone Deacetylase Inhibitor LAQ824 Augments Inflammatory Responses in Macrophages through Transcriptional Regulation of IL-10

Cited by 45 publications

References 51 publications

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

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

The role of myeloid cells in cancer therapies

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

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