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Regulation of immune responses by histone deacetylase inhibitors.

Licciardi PV, Karagiannis TC - ISRN Hematol (2012)

Bottom Line: There is an increasing body of evidence attesting to epigenetic modifications that influence the development of distinct innate and adaptive immune response cells.Chromatin remodelling via acetylation, methylation, phosphorylation, and ubiquitination of histone proteins as well as DNA, methylation is epigenetic mechanisms by which immune gene expression can be controlled.In particular, the role of HDAC inhibitors as a new class of immunomodulatory therapeutics will also be reviewed.

View Article: PubMed Central - PubMed

Affiliation: Allergy and Immune Disorders Group, Murdoch Childrens Research Institute, Melbourne, VIC 3052, Australia.

ABSTRACT
Both genetic and epigenetic factors are important regulators of the immune system. There is an increasing body of evidence attesting to epigenetic modifications that influence the development of distinct innate and adaptive immune response cells. Chromatin remodelling via acetylation, methylation, phosphorylation, and ubiquitination of histone proteins as well as DNA, methylation is epigenetic mechanisms by which immune gene expression can be controlled. In this paper, we will discuss the role of epigenetics in the regulation of host immunity, with particular emphasis on histone deacetylase inhibitors. In particular, the role of HDAC inhibitors as a new class of immunomodulatory therapeutics will also be reviewed.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of HDACi immunomodulation. (1) HDACi such as Trichostatin A and SAHA suppress the activity of class I/II HDAC enzymes (2). This reverses the acetylation status, leading to (hyper)acetylation of both (3) histone and (4) nonhistone proteins such as nuclear transcription factors. Together, chromatin remodelling and immune gene expression is altered and, in the context of the immune system, can lead to immunomodulation (5). Among the pleiotropic activities of HDACi, activation of Treg cells limits the extent of inflammatory-mediated tumourigenesis as well as the development of Th17 cells. HDACi also directly inhibit the activity of Th1 cells mainly by repression of the Th2 regulator, GATA-3. Inhibition of proinflammatory APC function is also mediated by HDACi by modulating NF-κB activation status. These properties of HDACi are also important in the immunosurveillance of cancer by upregulating specific markers that enhance tumour antigenicity and targeted immune system-mediated cytotoxicity CD8+ T cells and NK cells.
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fig1: Schematic representation of HDACi immunomodulation. (1) HDACi such as Trichostatin A and SAHA suppress the activity of class I/II HDAC enzymes (2). This reverses the acetylation status, leading to (hyper)acetylation of both (3) histone and (4) nonhistone proteins such as nuclear transcription factors. Together, chromatin remodelling and immune gene expression is altered and, in the context of the immune system, can lead to immunomodulation (5). Among the pleiotropic activities of HDACi, activation of Treg cells limits the extent of inflammatory-mediated tumourigenesis as well as the development of Th17 cells. HDACi also directly inhibit the activity of Th1 cells mainly by repression of the Th2 regulator, GATA-3. Inhibition of proinflammatory APC function is also mediated by HDACi by modulating NF-κB activation status. These properties of HDACi are also important in the immunosurveillance of cancer by upregulating specific markers that enhance tumour antigenicity and targeted immune system-mediated cytotoxicity CD8+ T cells and NK cells.

Mentions: The clinical use of HDAC inhibitors (HDACi) has been mainly focused on the treatment of cancer based on the documented antiproliferative activities involving regulation of gene expression, cell cycle arrest, apoptosis, and antiangiogenesis effects [2, 31–33]. Since the expression of HDACs influences the development and differentiation of immune responses, the identification of a variety of molecules able to inhibit particular HDAC enzymes (HDACi) offers an exciting and novel approach to the treatment of immune-mediated diseases (Figure 1). More specifically, HDACi with reported effects on autoimmune disease, transplantation, and infection will be discussed here in after.


Regulation of immune responses by histone deacetylase inhibitors.

Licciardi PV, Karagiannis TC - ISRN Hematol (2012)

Schematic representation of HDACi immunomodulation. (1) HDACi such as Trichostatin A and SAHA suppress the activity of class I/II HDAC enzymes (2). This reverses the acetylation status, leading to (hyper)acetylation of both (3) histone and (4) nonhistone proteins such as nuclear transcription factors. Together, chromatin remodelling and immune gene expression is altered and, in the context of the immune system, can lead to immunomodulation (5). Among the pleiotropic activities of HDACi, activation of Treg cells limits the extent of inflammatory-mediated tumourigenesis as well as the development of Th17 cells. HDACi also directly inhibit the activity of Th1 cells mainly by repression of the Th2 regulator, GATA-3. Inhibition of proinflammatory APC function is also mediated by HDACi by modulating NF-κB activation status. These properties of HDACi are also important in the immunosurveillance of cancer by upregulating specific markers that enhance tumour antigenicity and targeted immune system-mediated cytotoxicity CD8+ T cells and NK cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3313568&req=5

fig1: Schematic representation of HDACi immunomodulation. (1) HDACi such as Trichostatin A and SAHA suppress the activity of class I/II HDAC enzymes (2). This reverses the acetylation status, leading to (hyper)acetylation of both (3) histone and (4) nonhistone proteins such as nuclear transcription factors. Together, chromatin remodelling and immune gene expression is altered and, in the context of the immune system, can lead to immunomodulation (5). Among the pleiotropic activities of HDACi, activation of Treg cells limits the extent of inflammatory-mediated tumourigenesis as well as the development of Th17 cells. HDACi also directly inhibit the activity of Th1 cells mainly by repression of the Th2 regulator, GATA-3. Inhibition of proinflammatory APC function is also mediated by HDACi by modulating NF-κB activation status. These properties of HDACi are also important in the immunosurveillance of cancer by upregulating specific markers that enhance tumour antigenicity and targeted immune system-mediated cytotoxicity CD8+ T cells and NK cells.
Mentions: The clinical use of HDAC inhibitors (HDACi) has been mainly focused on the treatment of cancer based on the documented antiproliferative activities involving regulation of gene expression, cell cycle arrest, apoptosis, and antiangiogenesis effects [2, 31–33]. Since the expression of HDACs influences the development and differentiation of immune responses, the identification of a variety of molecules able to inhibit particular HDAC enzymes (HDACi) offers an exciting and novel approach to the treatment of immune-mediated diseases (Figure 1). More specifically, HDACi with reported effects on autoimmune disease, transplantation, and infection will be discussed here in after.

Bottom Line: There is an increasing body of evidence attesting to epigenetic modifications that influence the development of distinct innate and adaptive immune response cells.Chromatin remodelling via acetylation, methylation, phosphorylation, and ubiquitination of histone proteins as well as DNA, methylation is epigenetic mechanisms by which immune gene expression can be controlled.In particular, the role of HDAC inhibitors as a new class of immunomodulatory therapeutics will also be reviewed.

View Article: PubMed Central - PubMed

Affiliation: Allergy and Immune Disorders Group, Murdoch Childrens Research Institute, Melbourne, VIC 3052, Australia.

ABSTRACT
Both genetic and epigenetic factors are important regulators of the immune system. There is an increasing body of evidence attesting to epigenetic modifications that influence the development of distinct innate and adaptive immune response cells. Chromatin remodelling via acetylation, methylation, phosphorylation, and ubiquitination of histone proteins as well as DNA, methylation is epigenetic mechanisms by which immune gene expression can be controlled. In this paper, we will discuss the role of epigenetics in the regulation of host immunity, with particular emphasis on histone deacetylase inhibitors. In particular, the role of HDAC inhibitors as a new class of immunomodulatory therapeutics will also be reviewed.

No MeSH data available.


Related in: MedlinePlus