Targeting Transcription Factor Lysine Acetylation in Inflammatory Airway Diseases

Figures & data

Figure 1. Histone deacetylase classification.

(A) Zn²⁺-dependent HDACs. (B) NAD⁺-dependent HDACs.

HDAC: Histone deacetylase.

Figure 2. Schematic representation of the topics addressed in this review.

(A) Macrophages and various T lymphocytes have been implicated in inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease. These cell types depend on specific transcription factors for their differentiation and functionality. Histone deacetylases (HDACs) can affect the acetylation of these transcription factors, which influences, for example, the transcription factor stability or its DNA binding capability. HDAC inhibitors (HDACi) can influence these biological processes and thereby influence inflammatory responses by these cell types. (B) Effects of HDACi on histone acetylation are often used as a read-out indicative of the effects of these compounds in cells. However, histone acetylation is not sufficient to (fully) explain the effects of HDACi on biological processes such as gene expression. Effects of HDACi on transcription factors and their acetylation status may also be particularly important in explaining these effects. (C) Interestingly, selectivity profiles of HDACi are commonly elucidated by testing for inhibition of recombinant HDACs. Importantly, however, in cells HDACs are known to be present in multiprotein complexes that influence their activity. Importantly, recently, HDACi have been reported to have different specificities for such complexes, which adds another layer of complexity to the selectivity profile. (D) Different classes of HDACi have been reported to have different binding kinetics with the HDACs. Benzamine-based inhibitors have slow binding kinetics, while hydroxamate-based inhibitors have fast binding kinetics. This has been demonstrated to translate into biological consequences.

Table 1. The effects of histone deacetylase inhibitors on transcription factors and cell types implicated in lung inflammation models.

Transcription factor/cell type	Compound	Effects in lung inflammation models	Ref.
NF-κB/macrophages	HDAC1–3 inhibitor MS-275	Ambiguous effects	[66–71]
NF-κB/macrophages	HDAC3 inhibitor RGFP966	Attenuation of Inflammation	[74]
GATA3/Th2 cells	SIRT1 inhibitor Sirtinol	Increased Th2 related expression in T cells from cord blood; and in PBMCs from severe asthmatics Enhanced acetylation and activity of the GATA3 transcription factor in HUT78 T lymphocytes	[83]
GATA3/Th2 cells	SIRT1 activator (SRT2172)	Reduced IL-4 mRNA expression in PBMCs from ten patients with severe asthma	[83]
Foxp3/Tregs	HDAC6i ACY-738 and SIRT1 inhibitor EX-527	Increased Treg suppressive function (in combination and alone) EX-527 increased acetylation of K31, K262 and K267, and increased the stability and levels of the transcription factor	[91,96]
Foxp3/Tregs	HDAC1–3 inhibitor MS-275	Ambiguous effects	[98–100]
RORγt/Th17	HDAC1–3 inhibitor MS-275	Enhanced Th17 differentiation in mouse splenocytes	[106]
RORγt/Th17	Pan HDACi givinostat	Downregulated the IL-6 receptor on T cells that reduced their ability to differentiate into Th17 cells, but instead skewed differentiation toward the Treg phenotype	[107]
Foxp3 and RORγt	Pan HDACi TSA	Increased Foxp3 and decreased RoRγt levels in an ovalbumin challenge asthma mouse model	[38]

HDAC: Histone deacetylase; HDACi: Histone deacetylase inhibitor; PBMC: Peripheral blood mononuclear cell; TSA: Trichostatin A.

Table 2. IC₅₀ values of histone deacetylase 1–3-selective inhibitor MS-275 and histone deacetylase 3-selective inhibitor RGFP966 for recombinant class I human histone deacetylases.

HDAC inhibitor	HDAC 1	HDAC 2	HDAC 3	HDAC 8
MS-275^†	0.19 ± 0.04	0.41 ± 0.09	0.95 ± 0.19	76.5 ± 10.1
RGFP966^‡	5.6 ± 1.3	9.7 ± 1.8	0.21 ± 0.06	≥100

Data are presented as mean values (in μM) of three independent measurements ± SD. ND = not determined.

^†IC₅₀ values for MS-275 are taken with permission from [71].

^‡IC₅₀ values for RGFP966 are taken with permission from [74].

HDAC: Histone deacetylase; SD: Standard deviation.

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