Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, IL, USAUnited States
Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, IL, USA; Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo, EgyptEgypt
Also available as PDF (figures and tables appear in the PDF).
Early life exposure to a variety of insults during sensitive windows of development can reprogram normal physiological responses and alter disease susceptibility later in life. During this process, inflammation triggered by a variety of adverse exposures plays an important role in the initiation and development of many types of diseases including tumorigenesis. This systematic review article summaries the current knowledge about the role and mechanism of inflammation in development of diseases. In addition, epigenome alteration related to inflammation and treatment options using epigenetic modifiers are highlighted and discussed.
Keywords: Early life exposure; Environmental factors; Inflammation; Uterine fibroids; Epigenetic modifiers
nflammation is part of the biological response of body tissues
and defense mechanism to harmful stimuli. The immune sys-
I
tem recognizes damaged cells, irritants, and pathogens, and the
body is attempted to remove harmful stimuli and begin the healing
process.1 During the development, the environmental disruptors
create prolonged inflammation status, and increase the risk of ge-
nomic instability and the introduction of novel mutations. Sev-
eral signaling pathways involved in the regulation of inflammatory
response have been described under the control of epigenetics.
Therefore, inflammation is well recognized as a hallmark feature
linked to the development of many diseases including varied types
2-10 of tumors.2-10 Inflammatory cells and cytokines in the local tissue
microenvironment promote a pro-inflammatory milieu, which can
act in an autocrine and/or paracrine manner on the infiltrating im-
mune cells and modified malignant cells. Thus the composition
of the inflammatory microenvironment has a pivotal influence on
risk of disease development and progression.2 In the case of tu-
mors, inflammation switches to immunosuppression due to tumor
evasion from anti-tumor immune response. A promising approach
cc Copyright 2018 by Yang Q. This is an open-access article distributed under Creative Commons Attribution 4.0 International License (CC BY 4.0), which allows
to copy, redistribute, remix, transform, and reproduce in any medium or format, even commercially, provided the original work is properly cited. for reversing the tumor immune evasion phenotype is epigenetic
therapy, which exhibit efficacy in patients with refractory advanced
non-small cell lung cancer. In this study, the epigenetic therapy was
able to increases the numbers of activated immune cells in a mouse
model of ovarian cancer. The goal of this systematic review is
to summarize the available information on the therapeutic effect
of epigenetic agents, which are able to reverse pro-inflammatory
phenotype of diseases.
Inflammation plays an important role in the initiation and devel-
opment of much type of diseases including cardiovascular dis-
ease, diabetes, mental health dysfunction, and certain types of
12,13 cancer. Several perinatal environmental factors including nu-
trition, stress, air pollution, antibiotics can cause and increase the
risk of adult diseases via inflammation (Figure 1). An association
between early life inflammation and later life diseases has been
14-18 reported in many literatures. Epidemiological studies have
highlighted the link between perinatal factors (such as breastfeed-
ing, cesarean delivery, and antibiotic use) and an increased risk
for inflammatory bowel disease and/or celiac disease. Perinatal
environment determines susceptibility to intestinal inflammatory
disorders. Although the mechanisms underlying joint effects re-
main unclear, one hypothesis is that toxic social and environmen-
tal exposures have synergistic effects on inflammatory processes
that underlie the development of chronic disease.20 During ma-
ternal obesity along with increased inflammatory markers in the
maternal circulation, increased placental production of pro-in-
flammatory mediators can be found, suggesting that the resulting
inflammatory milieu where the fetus develops may have critical
consequences for later diseases such as obesity.21 The association
between prenatal undernutrition and later-life metabolic disor-
ders has been well established in multiple animal studies. For
instance, placentas from protein-restricted rats exhibit a marked
reduction of 11-β-hydroxysteroid dehydrogenase 2 enzyme
(11-β-HSD2), which leads to fetal exposure to abnormally high
glucocorticoid levels during gestation and later hypertension in
the adult offspring.23 During this process, pro-inflammatory cyto-
kines can cause decreased activity of 11-β-HSD2, and thus may
play a role in programming by maternal diet.24 Similarly, prenatal
cytokine exposure is sufficient to induce obesity later in life.
Epigenetics refers to changes in phenotype mediated by altered
gene expression. These changes do not occur as a result of the
alteration in DNA sequencing.26 DNA methylation and histone
modification are the two major epigenetic mechanisms, which
collaborate to package genes in euchromatinor heterochroma-
tin, a packaging that determines whether a gene is activated or
silenced. DNA methylation refers to the covalent addition of a
methyl group to a cytosine residue in a CpG dinucleotide. His-
tone modification is a covalent post-translational modification
(PTM) to histone proteins, which includes methylation, acetyla-
tion, phosphorylation, ubiquitylation, and sumoylation. The his-
tones with varied PTMs can impact gene expression pattern by
changing chromatin structure or recruiting histone modifiers. Hy-
permethylation of promoter CpG islands is linked with repressive
transcriptional activity because of loss of affinity for transcrip-
tional factors and accessibility by the transcriptional machinery.
The crosstalk between DNA methylation and histone modifica-
tion has also been discovered. The heterochromatin has increased
affinity for methylated DNA-binding proteins (MBPs), which fur-
ther recruit other transcriptional corepressors including histone
deacetyltransferases (HDACs), DNA methylases (DNMTs,), etc.
Hypermethylation of promoter regions is associated with repres-
sive histone marks, while unmethylated promoters are associated
with active histone marks. Under latter circumstance, the gene
expression is activated, since affinity for MBPs is reduced, and
enrichment for activate histone marks is increased.
An increased body of evidence shows that a variety of
pro-inflammatory mediators is regulated via epigenetic mecha-
nism, which contributes to pathogenesis of diseases. A recent
study by Li et al demonstrates that epigenetic regulation of ke 19 Figure 1. Early Life Exposure to a Variety of Insults Increases the Risk and De-
velopment of Diseases in Later Life via Inflammatory Pathway by Reprogram-
ming the Epigenome. Epigenetic Modifiers Targeting Inflammatory Pathways
are Capable of Inhibiting the Pro-inflammatory Phenotype,Therefore Leading to Suppressing/Preventing the Development of Diseases.
22,23
24,25
ratinocytes can contribute to chronic skin inflammation.34 Actin
polymerizing molecule N-WASP is capable of modulating inter-
leukin IL-23 expression in keratinocytes by regulating the degra-
dation of the histone methyltransferases G9a and GLP, as well as
H3K9 dimethylation level of the IL-23 promoter. This mecha-
nism mediates the induction of IL-23 by tumor necrosis factor
(TNF-α), a known inducer of IL-23 in psoriasis.34
During a plastic interval of the prenatal and neonatal
segments of life, a stable reprogramming of gene expression can
35-37 occur and may predispose the individuals to adult disease. At
a molecular level, epigenetic processes including DNA methyla-
tion and histone modifications constitute a major mechanism
by which environmental factors may establish a new phenotypic
trait during this plastic interval.38 A recent study demonstrates
that preterm infant outcomes are associated with modulation of
host immune and inflammatory responses, which are impaired by
acute intrauterine and microbiota factors. The latter one plays a
pivotal role in maturation of the immune system and in the pre-
39,40 vention or development of diseases occurring during lifetime.
Concomitantly, prenatal inflammatory exposure results in hyper-
methylation of promoter regions for TLR-signaling pathways,
which play a role in the innate immune response.35
Several clinical studies have shown that epigenetics may
be involved in the pathogenesis of chronic inflammatory diseases.
In the intestinal mucosa of celiac disease patients, DNA methyla-
tion play a role in regulating the NF-kB pathway, associated with
dysregulation of the inflammatory response.19 Activation of NF-
kB has been shown to elevate the expression of genes encoding
for cytokines, chemokines, and other pro-inflammatory media-
27-33 20,41 tors such as IL-6, IL-8. In addition, early-life stress has been
associated with modification of hypothalamic-pituitary-adrenal
(HPA) axis- and neuroplasticity-related methylations. Changes in
DNA methylation status of glucocorticoid receptor (GR) gene, a
key regulator of inflammatory activity and others, was observed
in response to early life stress.42
In addition to DNA methylation, histone modification
has been reported to be associated with regulation of pro-inflam-
matory phenotype and adult disease due to early life insults. For
example, an animal study demonstrates that the promoter of gene
(GR/NR3C1) that encodes the GR, which play an important role
in creating a pro-inflammatory environment, exhibits differential
levels of histone acetylation as well as DNA methylation in the
hippocampus of offspring of high versus low licking and groom-
ing (LG) and arched-back nursing (ABN) mothers. Importantly,
central infusion of the HDAC inhibitor (TSA) is capable of el-
evating H3K9 acetylation and hypermethylation of GR promoter
with increased NGF1-A binding, GR expression as well as HPA
response to stress in the offspring of the low-LG-ABN moth-
ers.42
Uterine fibroids (UFs) are hormonally-regulated benign smooth
muscle myometrial tumors that severely affect female repro-
ductive health, although their unknown etiology limits effective
43,44 care. An increasing body of evidence supports the hypothesis
that UFs originate from stem cells in the myometrium, although
the specific cell of origin for these tumors has remained elusive.45
Myometrial stem/progenitor cells (MMSCs) and UF stem/pro-
genitor cells (UFSCs) have been identified. MMSCs are a sub-
set of cells residing in the uterine myometrium, that remain their
capacity to self-renew through asymmetric division rates as well
as producing differentiated cells, which play an important role in
tissue regeneration. UFSCs represent a subgroup of cells with a
tumor cell population, which also retain the ability to reconstitute
tumors.50 Notably, the difference between MMSCs and UFSCs
at DNA level is that MED12 mutations were found only in UF-
SCs, but not MMSCs. In addition, the defect of DNA repair re-
sponse was recently observed in UFSCs.51 In UFs, a recent study
shows that higher numbers of macrophages are present inside
and close to UFs as compared to the more distant myometrium.52
Notably, several key pro-inflammatory mediators including IL-
11, IL-13 and TGF-β are overexpressed in UFs. The latter one
in particular is a potent chemoattractant factor for macrophages.
Another group has reported that many pro-inflammatory media-
tors that trigger or enhance specific aspects of inflammation are
upregulated in UF tumors as compared to adjacent myometrium
tissues.50 In addition, the levels of tumor necrosis factor TNF-α,
a cell-signaling protein involved in systemic inflammation, is el-
evated in Caucasian women with clinically symptomatic UFs.53 A
recent study also shows that UF progenitor cells secrete higher
levels of Th2 pathway cytokines (IL4, IL-5, IL-10, and IL-13),
and significantly lower levels of Th1/Th17 cytokines (IL-6, IL-
12, IL-17A, INF-γ, G-CSF, and TGF-β1), suggesting that the al-
tered pattern of cytokine expression and secretion may enhance
UF development via chronic inflammation with the involvement
of infiltrating immune cells.54 The link between UF development and early life expo-
sure to xenoestrogen via inflammation has been recently iden-
tified in Eker rat animal model.55 The adult Eker rats develop-
mentally exposed to diethylstilbestrol (DES) exhibits significantly
higher expression of pro-inflammatory markers (TNF-α, NF-
kB and IL1β) in myometrium. Concomitantly, the macrophage
number is also significantly increased in DES-exposed myome-
trium in adult stage. Flow cytometry analysis demonstrates that
the production of several inflammatory cytokines is increased in
DES-MMSCs verse vehicle exposed (VEH)-MMSCs. By RNA- se-
quencing analysis, some of key pro-inflammatory genes including
Pcdh7, Pdpn, Cxcl10, Cd40, Ptger2, and Ereg, exhibits upregula-
tion in MMSCs from myometrium early-life exposed to (DES)
verse control (VEH). Subsequently, gene set enrichment analysis
on the ChIP-sequencing data demonstrates that an enrichment
of H3K4me3 (an active mark for gene transcription) at the pro-
moters of inflammation responsive genes (IRGs) is observed in
DES-MSCs as compared to VEH-MMSCs. Furthermore, the in-
creased expression of IRGs in DES-MMSCs is positively cor-
related with the elevated H3K4me3 epigenetic mark. In addition,
the mRNA expression of reprogrammed key cytokine genes en-
coding CCL-2, CCL-7, CSF-1, which contribute to the recruit-
ment of monocytes/macrophage, exhibits a significant upregula-
tion in DES-MMSCs verse VEH-MMSCs. These studies suggest
that developmental exposure to xenoestrogens such as DES alters
the inflammatory microenvironment in the myometrium and in-
creases the risk of adult onset of UFs by permanently reprogram-
ming pro-inflammatory genes in MMSCs towards a pro-fibroid
epigenomic landscape.55
46-49
Epigenetic modifiers/agents targeting DNMTs and histone mod-
ified enzymes have been widely investigated in preclinical studies
of many diseases. Moreover, a variety of studies demonstrate that
these epigenetic modifiers suppress and ameliorate varied dis-
eases including immunopathogenesis, tissue damage, pain, bone
32,56-61 and cartilage destruction, and cancers, etc. via inflammation
(Table 1).
The zinc-dependent mammalian histone deacetylase
(HDAC) family comprises over 10 enzymes, which have specific
and critical functions in development and tissue homeostasis. In-
creased evidence points to a link between misregulated HDAC
activity and many oncologic and non-oncologic diseases. Thus,
the development and usage of HDAC inhibitors provide a prom-
ising option for therapeutic treatment. Currently, the effect of
HDAC inhibitors on suppression of diseases via anti-inflamma-
tory pathway has been widely investigated both in vitro and in vivo.
As shown in table 1, most of the epigenetic modifiers targets
inflammatory pathway by inhibition of HDAC activity, therefore
leading to suppression of diseases via inflammatory pathway.
HDAC inhibitors effect that contributes largely to their therapeu-
tic benefits, is achieved through histone deacetylation, chromatin
remodeling and transcriptional reprogramming, as well as other
unknown or not fully characterized mechanisms.
Table 1. The Anti-Inflammatory Effect of Epigenetic Agents
Dihydrocaffeic acid Plasma pro-
(DHCA) inflammatory Chronic stress/ Mouse model of sys- introns 1 and 3. 82 Phytochemicals -Malvidin-3’-O-gluco- interleukin 6 depression temic inflammation -Mal-gluc increased histone acety-
side (Mal-gluc) (IL-6) level
Pan-selective Human macro- JIB-04 Atherosclerosis RAW264.7 cells macrophages in a dose-dependent KDM inhibitor phages
Selective
inhibitor of the
bromodomains Human Th17 CBP30 as ankylosing patients with anky- 17A and other pro-inflammatory of CBP (CREB cells
binding protein)/
p300
Bromodomainex- GSK151 inflammatory of Experimental oral gavage for 5 days 72 traterminal (BET) Th17 cells -JQ1 disease: Poste- autoimmune uveitis 20 mg/kg inhibitors
Bromodomainex- GSK151 Human Th17 inflammatory Human CD4+ Th17-associated genes IL-17A, 72 traterminal (BET) -JQ1 cells disease: Poste- T- cells IL-22, and retinoic acid–related inhibitors
BD1-selective
MS402 BET bromodo- Mouse model and ameliorates T-cell transfer- at week 0, or week
main inhibitor
Histone deacety- Systemic lupus Cultured Human IL-10.
TrichostatinA (TSA) lase (HDAC) T-cells erythematosus peripheral blood -TSA reversed the skewed expres-
inhibitor (SLE) mononuclear cells sion of multiple genes implicated
TrichostatinA (TSA) HDAC inhibitor macrophages (LPS)-induced mouse changes and inflammationdue to
TrichostatinA (TSA) HDAC inhibitor from PBMC healthy pression of IL-1 β, IL-6 and tumor 5 μM for 4 hours
TrichostatinA (TSA) Rheumatoid from the inflamed 87 HDAC inhibitors Macrophages -Nicotinamide (NIC) arthritis joints of patients
Streptococcus ITF2357 SCW fragments into of 1 and 10 mg/kg 88 HDAC inhibitor pyogenes cell Acute arthritis (Givinostat) the right
ITF2357 HDAC inhibitor PBMCs A-induced Mouse model -ITF2357 reduced LPS-induced (Givinostat)
Suberoylanilide-
hydroxamic acid Mouse macro- Inflammatory HDAC inhibitor (SAHA) phages diseases
(Vorinostat)
HDAC3 selective Rheumatoid MI192 PBMCs assay, prior to and at high concentrations and dose- μM-5 nM for 18 inhibitor arthritis(RA)
DHCA inhibited DNA methylation Orally at the CpG-rich IL-6 sequences -Mal-gluc (0.5μg/kg/
day)
-DHCA (5 mg/kg/day) lation of the regulatory sequences for 24 days of the Rac1 gene.
JIB-04 induced apoptosis of 1 μM JIB-04 for 24 83
hours manner.
Human type-
17–mediated Th17 cells from
diseases such healthy donors and CBP30 reduced secretion of IL- 2 μM CBP30 for 24 84
hours spondylitis losing spondylitis and cytokines.
and psoriatic psoriatic arthritis
arthritis
Intraocular Mouse model Both abrogated the uveitogenic
capacity of Th17 cells to transfer
EAU.
rior uveitis (EAU)
Intraocular Both significantly downregulated JQ1 (30, 300 nM) or
GSK151 (30, 300 nM)
for 5 days rior uveitis orphan receptor γt.
10 mg/kg twice a
MS402 blocked Th17 maturation week starting either Mouse naive Inflammatory 73
CD4+T cells bowel diseases induced colitis. 5 for 7 or 3 weeks,
respectively
TSA Downregulated CD40L and
0-1000 ng/ml for 18 59
hours
in the immunopathogenesis of SLE.
TSA caused substantial attenuation
Lipopolysaccharide of adverse lung histopathological Acute lung 1 μg/g body weight 85
injury (ALI) for 2 weeks of ALI substantial macrophage phenotypic
changes.
peripheral pathogenic LPS-stimulated TSA down-regulated mRNA exblood mono- microorganisms 86
nuclear cells induced inflambroilers necrosis factor alpha (TNF-α).
(PBMC) mation
Macrophages derived Both Blocked the production of TSA (2 μM)
IL-6 and TNF-alpha by macro- NIC (20 mM)
phages. for 4 hours with RA
Injection of 25 μg Oral administration ITF2357 reduced the production
of pro-inflammatory cytokines by knee joint ITF2357 at 2 hours,6 wall arthritis synovial tissue.
of C57/Bl6 mice hours, day 1 and day 2
ITF2357 significantly reduced liver
Concanavalin- damage.
Oral 1 or 5 mg/kg 89
one time hepatitis serum TNF-alpha and interferon
gamma (IFN-γ) by more than 50%.
-50 mg/kg single oral -In vivo animal model - Both reduced the production of or IV administration 90 pro-inflammatory cytokines TNFof SAHA to mice -In vitro. alpha, IL-1-beta, IL-6, and IFN-γ.
-200 nM for 1 hour
RA patients by
spectrophotometric MI192 inhibited TNF production Dose range of 10
after 12 weeks of dependently inhibited IL-6 in RA. hours.
Etanercept therapy.
Cont...
Valproic acid (VPA) HDAC inhibitor thritis (CIA) mouse ing on day 21 of the
Naturalpolyphe-
nol extracted Hepatocellular
Curcumin from turmeric, carcinoma cell
pan-HDAC line
inhibitor
HDAC and p300/ Human lym-
Curcumin CBP-specific phoma cell line Lymphoma
inhibitor (Raji)
Natural polyphe-
nol extracted
Curcumin from turmeric, HepG2.2.15 cell line 20 μmol/L for 2 days
pan-HDAC
inhibitor
-Minocycline Histone acetylacultured retinal Diabetic retition (HAT) inhibi- Diabetic rats -Both significantly inhibited the
-Garcinol tor
-Theophylline Activators of his- cultured retinal Diabetic reti-
-Resveratrol tone deacetylase Müller glia nopathy
-MS-275 (Entinostat) Peripheral rats inflamed by subclass I HDAC spontaneous -MGCD0103 (Mo- inflammatory cutaneous injection inhibitors nociception cetinostat) pain of bee venom (BV)
Natural indoles- -Indole-3-carbinol Staphylococcal found in crucifer- (I3C) enterotoxin B ous vegetables, Vβ8(+)T cells In vivo animal model SEB-inducedT cell activation and other day for up to -3,3’-diindolylmeth- (SEB)induced inhibitors of ane (DIM) inflammation HDAC class I
Depsipeptide Rheumatoid HDAC inhibitor Synovial tissues autoantibody-medi- destruction in mice with AMA. intravenous dose on (FK228) arthritis
-Prostate tissue -Experimental cumulation of immune cells and
MS-275 HDAC inhibitor titisrats pro-inflammatory molecules.
Panobinostat HIV-associated HDAC inhibitor PBMCs HIV-infected adults per week, every other (LBH589) inflammation
Monocyte-de-
Sulforaphane (SFN) HDAC inhibitor rived dendritic Porcine cells TGF-ß1 production 10 μM for 24 hours VPA treatment increased both the Collagen-induced ar- 400 mg/kg daily startregulatoryT Rheumatoid suppressive function of CD4(+), 92
cell (Tregs) arthritis. CD25(+)Tregs and the numbers of model study till day 60 CD25(+),FOXP3(+)Tregs in vivo.
Curcumin had CSC-depleting Hepatocellular Cancer stem cells 93 activity attributed to a NF-κB- 25 μM for 3 days carcinoma (CSCs) mediated HDAC inhibition.
Curcumin prevented degradation
of I-kappaB alpha and inhibits
Human cancer cell nuclear translocation of the 12.5 μmol/L for 24 94
line NF-kappaB/p65 subunit, as well as hours
expression of Notch 1, induced by
tumor necrosis factor-alpha.
covalently Curcumin inhibited HBV gene
closed cir- Hepatitis B replication via down-regulation of 95
cular DNA virus infection cccDNA-bound histone acetyla-
(cccDNA) tion.
- Both inhibited early diabetic reti- -10 mg/kg, i.p. injecnopathy via decreased expression tion, 5× per week for of inflammatory proteins.
10 weeks 96
Müller glia nopathy - 20 μm Garcinol for acetylation and induction of the 24 hours, 20 nM Miinflammatory proteins in elevated nocycline for 4 days glucose levels.
Both significantly inhibited the
acetylation and induction of the -10 μm for 4 days. 96 Diabetic rats inflammatory proteins in elevated -50 μm for 24 hours
glucose levels.
persistent
Both prevented peripheral inflam- Intrathecal single dose 60
matory pain. of 60 nmol/20 μL
(PSN)
Both significantly decreased 40 mg/kg, i.p. every
cytokine production. 5 days
-FK228 inhibited joint swell-
ing, synovial inflammation, and
Animal model of subsequent bone and cartilage 2.5 mg/kg single
ated arthritis - FK228 decreased the levels of day 4
tumor necrosis factor alpha and
interleukin-1beta.
- MS-275 reduced the local ac-
autoimmune prosta- mRNA levels of representative Chronic pros- 5 mg/kg, i.p. daily from 99
tatitis day 0 to day 14 Macrophages - MS-275 switched macrophages
-Macrophage cell line from classic M1 to anti-inflamma-
tory M2 phenotype
- LBH589 reduced multiple
established plasma markers of
inflammation as high-sensitivity
C-reactive protein, matrix metal- 20 mg three times loproteinase 9, soluble CD40 100
ligand and IL-6.
week, for 8 weeks - LBH589 reduced the propor-
tions of intermediate mono-
cytes and tissue factor-positive
monocytes.
-SFN regulated the TLR4-induced
activity of transcription factor
NF-κB and TBP
-SFN suppressed the IRF6 and Systemic inflam- 101
mation cells -SFN impaired the pro-inflamma-
tory cytokine TNF-α and IL-1ß
secretion into the cell culture
supernatants.
Cont...
class III HDAC Endothelial skin inflamma- Sirtinol microvascular endo- 10 μM for 18 hours inhibitor cells tion
DNA methyl
5-Aza 2-deoxycyti- transferase Acute lung LPS-induced mouse 1 μg/g body weight 85
dine (Aza) (DNMT) inhibi- injury (ALI) of
tor
Cambinol HDAC inhibitor macrophages
Novel HDAC Human mono- Rheumatoid NW-21 In vitro 20 nM for 24 hours inhibitor cytes arthritis
Novel HDAC Radiocarpal Rheumatoid NW-21 induced arthritis tion at 5 mg/kg/day till inhibitor joint arthritis
Benzamide ease associated Immortalized murine MS-275 attenuated inflammatory 20 ng/mL for 24 105 MS-275 Macrophage HDAC inhibitor neuroinflam- macrophage cell line activation of a mouse macrophage. hours
Sciatic nerves inflammatory Experimental 3.5 mg/kg, i.p. once a
MS-275 HDAC inhibitor and inguinal demyelinating autoimmune neuritis day from day 10 to
HDAC6 selective Rheumatoid Tubastatin macrophages inhibitor Arthritis Freund’s complete
The Bromodomain and Extra-Terminal Domain (BET)
family proteins play a crucial role in regulating gene transcription
through epigenetic interactions between bromodomains and acet-
ylated histones during cellular proliferation and differentiation
processes.62 Bromodomains that can specifically bind acetylated
lysine residues in histones serve as chromatin-targeting mod-
ules that decipher the histone acetylation code. BET inhibitors
that are capable of targeting BET bromodomains and exhibiting
therapeutic effects have been described. Notably, emerging
evidence suggests that BET proteins are involved in pathogen-
esis of inflammatory diseases62 and BET inhibitors exhibit potent
anti-inflammatory effectsin several types of diseases. In the brain
of the Alzheimer’s disease animal model, the BET inhibitor JQ1
decreases neuroinflammation with a reduction in the expression
of the pro-inflammatory modulators IL-1b, IL-6, TNF-α, CCL-
2, NOS-2 and PTGS-2 in the brain of mice.71 In addition, BET
inhibitors are capable of inhibiting retinal inflammatory disease
72,73 and inflammatory bowel diseases.
Sirtinol significantly reduced human dermal membrane expression of adhesion 102
molecules in TNFα- or IL-1βthelial cells stimulated cells.
Aza caused substantial attenuation
of adverse lung histopathological
Macrophages changes and inflammationdue to ALI for 2 weeks substantial macrophage phenotypic
changes.
Cambinol inhibited the expression Inflammatory Bone marrow de- 12.5, 50 μM for 1 103 of cytokines (TNF, IL-1β, IL-6, ILdiseases rived macrophage hour 12p40, and IFN-γ).
NW-21significantly reduced
mRNA expression of mono-
cyte chemotactic protein 1 and 104
macrophage inflammatory protein
1α in monocytes stimulated by
lipopolysaccharide or TNF-α.
NW-21reduced inflammation and collagen antibody- daily oral administrabone loss in the arthritis modelus- 104
ing paw inflammation scoring, animal model end of study histology and live animal micro-CT.
Alzheimer dis-
mation
- MS-275 reduced the severity and
duration of EAN and attenuated
local accumulation of macro-
phages,T cells and B cells.
Human - MS-275 reduced mRNA levels
of pro-inflammatory interleukin- 106
1beta, interferon-gamma and lymph nodes polyradiculo- mice day 14 interleukine-17.
neuropathies - MS-275 increased expression of
anti-inflammatory cytokine inter-
leukine-10 and anti-inflammatory
M2 macrophages in sciatic nerves.
THP1 cells -Tubastatin inhibited TNF-α and
IL-6 in LPS stimulated human THP- 272 nM and 712 nM
1 macrophages. for 24 hours
-Tubastatin significantly inhibited 30 mg/kg i.p. for 5 adjuvant (FCA) inof IL-6 in paw tissues of arthritic days duced animal model mice.
of inflammation
In addition to targeting HDACs and BET proteins, the
inhibitors of DNMTs have been widely used in many pre-clinical
studies for a variety of diseases, as well as in some clinical ap-
74-79 plication. The approved anti-DNMTdrugs 5-azacitidine (5AC)
and 5-aza-2’-deoxyazacytidine (DAC) are in clinical use for the
treatment of myelodysplastic syndrome of all types and chronic
myelomonocytic leukemia.80 The inflammation related studies in
Tumor initiation and disease development via inflammatory path-
way are linked with early life exposure to a variety of adverse in-
sults via epigenetic reprogramming, which play an important role
in alteration of pro-inflammatory profiling and phenotype. Much
more attention is needed to identify epigenetic agents, which ex-
hibit potent anti-inflammatory effect with minimum of side ef-
fects. In addition, more studies are needed to evaluate the role of
epigenetic-based drugs alone or in combination with other chem-
ical agents in suppressing inflammation as a means of prevention
and management of many diseases including UFs.
None of the authors has a financial relationship with a commer-
cial entity that has an interest in the subject of this manuscript.
This study was supported in part by the National Institutes of
Health grants: R01 HD094378, R01 ES028615.