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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
HDAC enzymes could help control Th1 and Th2 differentiation of naive CD4+ T cells by reversing the hyperacetylation of histones three and four at the IFN-γ promoter (Licciardi and Karagiannis, 2012). Moreover, HDACs are also involved in the balance of inflammatory responses mediated by IL-6, IL-8, IL-1β, and GM-CSF by regulating the histone acetylation status of NF-κB and AP-1 (Licciardi and Karagiannis, 2012; Gatla et al., 2019). HDAC inhibitors entinostat and valproic acid (VPA) have been shown to impair poly-I:C-stimulated DC activation in vitro, thereby decreasing the nuclear RelB, IRF-3 and IRF-8 (McCaw et al., 2017). The pan-HDAC inhibitor Panobinostat reduces antigen uptake, expression of costimulatory molecules and production of Th1 polarizing inflammatory cytokines by poly-I:C-stimulated DCs, which in turn impairs the differentiation of IFN-γ–producing T cells (McCaw et al., 2017).
Role of regulatory T cells in mucosal immunity
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
DCs can be further divided into two subsets, DC1 and DC2, based on CD11b expression. CD103+CD11b+ DCs (DC2) are the most prominent DCs in the small intestine but are less abundant in the colon and uncommon in other tissues. The development of CD103+CD11b+ DCs is dependent on Notch2 and IRF4. Although CD103+CD11b+ DCs are a major constituent of the tolerogenic CD103+ DC population, depletion of this subset does not affect the number of intestinal Treg cells. CD103+CD11b− DCs (DC1) are functionally related to splenic CD8α+ DCs. Their development is dependent on the basic leucine zipper transcription factor ATF-like 3 (Batf3) and IRF8, and they can efficiently cross-present internalized soluble or cell-associated antigens to naïve CD8+ T cells. CD103+CD11b− DCs express high levels of RALDH and as such contribute to intestinal pTreg development together with the CD103+CD11b+ DCs. Mice lacking both CD103+CD11b+ and CD103+ CD11b− DC subsets have reduced numbers of intestinal Treg cells.
Monocyte and lymphocyte membrane markers: Ontogeny and clinical significance
Published in Gabriel Virella, Medical Immunology, 2019
Scott Sugden, Damien Montamat-Sicotte, Karen K. Yam, Joseph Murphy, Bader Yassine Diab, Virginia Litwin
One of the key players of monopoiesis is the transcription factor PU.1. High expression of PU.1 will lead to the activation of different myeloid specific factors such as interferon regulatory factor-8 (IRF8), kruppel-like factor 4 (KLF-4), and Erg1. PU.1 expression is also indispensable to the expression of macrophage colony stimulating factor receptor (M-CSFR, CD115). Macrophage colony stimulating factor (M-CSF) and IL-34 are two ligands for CD155 crucial to monocyte development.
CD11c+ and IRF8+ cell densities in rectal cancer biopsies predict outcomes of neoadjuvant chemoradiotherapy
Published in OncoImmunology, 2023
Benita C. Y. Tse, Sarah Bergamin, Pascal Steffen, George Hruby, Nick Pavlakis, Stephen J. Clarke, Justin Evans, Alexander Engel, Andrew Kneebone, Mark P. Molloy
High IRF8 expression in the context of other solid cancers has also been associated with beneficial effects. In grade 2 and 3 estrogen-receptor negative breast cancers, IRF8 protein expression can predict response to trastuzumab treatment and patients with high IRF8 expression have prolonged recurrence-free survival30. Similarly, analysis of TCGA data for renal cell carcinoma showed that patients with high IRF8 expression had improved DFS31. Patients with high IRF8 in metastatic sites also had prolonged overall survival. These studies, however, did not directly demonstrate that immune cell populations were responsible for the elevated IRF8 expression. Here, we show that high IRF8+ cell density is associated with prolonged DSS in LARC. Of interest, 10 out of the 16 patients had an inverse relationship between IRF8+ cell and CD11c+ cell densities (i.e. high IRF8+ and low CD11c+ cell density or low IRF8+ and high CD11c+ cell density). This suggests that patients with a combined high IRF8+ and low CD11c+ cell densities may achieve the greatest survival outcomes. Future studies with larger cohorts are required to confirm the association of myeloid cell densities and patient survival and will be able to dissect the relationship between these myeloid cell populations in greater detail.
Altered expression of transcription factors IRF4 and IRF8 in peripheral blood B cells is associated with clinical severity and circulating plasma cells frequency in patients with myasthenia gravis
Published in Autoimmunity, 2018
Yong Zhang, Xiao Jia, Yan Xia, Hao Li, Fei Chen, Jie Zhu, Xiuying Zhang, Yanyan Zhang, YuZhong Wang, Yanan Xu, Meng Pan, Xiaoyu Huang, Tingyan Yu, Linlin Fu, Chenghua Xiao, Deqin Geng
The interferon regulatory factor family of transcription factor (IRF) consists of nine mammalian members that are important regulators of both immunity and other physiological processes [6]. Two members of this family, IRF4 (also known as Pip, LSIRF, LCSAT and MUM1) and IRF8 (also known as ICSBP) are unique in that they are highly homologous to each other rather than to other IRF family members and they are expressed exclusively in the immune system [7]. The roles of IRF4 and IRF8 in immune system development and function have been well-documented. For example, IRF4 play key roles in generation and functions of Th1/Th2/Th17/Tfh/Th9, macrophages and dendritic cells [8–14]. Similarly, IRF8 is important for Th1/Th17, macrophage and dendritic cell development and function [15–19]. In B cells specifically, IRF4 and IRF8 are expressed at multiple stages and have been shown to be critical for pre-B cell development, receptor editing, germinal center (GC) reaction and plasma cell differentiation [20–27]
Inhibition of anti-viral responses in intestinal epithelial cells by epigenetic modifying drugs is mediated by a reduction in viral pattern recognition receptor expression and activity
Published in Immunopharmacology and Immunotoxicology, 2019
Conor Hennessy, Sarah O’Connell, Laurence J. Egan, Declan P. McKernan
There is research which shows that IRF8 acts as a negative regulator of TLR3 (Fragale et al., 2011), suggesting that by binding to the TLR3 promoter and inhibits its transcription. We hypothesized that IRF8 expression may be related to the changes in TLR3 expression and function. To this end, we measured IRF8 mRNA expression in the WT and DKO HCT116 cells (Figure 5(A)). We determined that knockout of the DNMTs results in increased IRF8 expression (17 fold increase, p < .01). This effect was also seen in the 5-aza-2-dc treated HCT116 cells (24 fold increase, p < .01) (Figure 5(B)), and the SAHA treated cells (24 fold increase, p < .001)(Figure 5(C)). In order to provide evidence that IRF8 is potentially the cause of the changes in TLR3 following the epigenetic modifications induced by both DNMT and HDAC inhibition, we overexpressed IRF8 in the cell line. We observed the expected response of the WT cells to the poly I:C stimulation, which a large increase in TLR3 mRNA expression observed (Figure 5(D), 6 fold increase, p < .001), in line with our previous findings. However, following transfection of the HCT116 cells with hIRF8, we noted an overall decrease in TLR3 expression, inhibiting the typical poly I:C induced upregulation of TLR3 (p > .05 for all groups vs. UT). Furthermore, when we examined IFNβ mRNA, we determined that the overexpression of IRF8 was also inhibiting the poly I:C induced cytokine upregulation (Figure 5(E), p > .05 vs. UT in all hIRF8 overexpression groups). As is evident from Figure 5(F), the overexpression was extremely effective, with increases in IRF8 expression seen following transfection (over 200,000 fold increase in expression in all groups, p < .001 vs. untransfected for all groups). Thus, these results would suggest that IRF8 is capable altering the function of TLR3.