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Molecular M echanisms in C orticosteroid R esistance ; H istone A cetylation and D eacetylation. Hasan Bayram, MD, PhD . Department of Chest Diseases , School of Medicine , University of Gaziantep E-mail: bayram@ gantep .edu.tr. - PowerPoint PPT Presentation
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Molecular Mechanisms in Corticosteroid Resistance; Histone
Acetylation and Deacetylation
Hasan Bayram, MD, PhD.Department of Chest Diseases, School of
Medicine, University of Gaziantep E-mail: [email protected]
TTS 15th Annual Congress, Antalya 11-15 April 2012
• I have no conflict of interest to declare with regards to my presentation.
Contents• How do steroids work?• How does steroid resistance occur?• Histone acetylation and deacetylation• HDAC abnormality in diseases• The effect of increased HDAC activity in
treatment• Summary
Glucocorticoid Activation of Anti-inflammatory Gene Expression
Barnes PJ, J Steroid Biochem Mol Biol. 2010
Glucocorticoid Suppression of Activated Inflammatory Genes
Barnes PJ, J Steroid Biochem Mol Biol. 2010
Possible Molecular Mechanisms of Steroid Resistance
Barnes PJ, J Steroid Biochem Mol Biol. 2010
Mechanism of Glucocorticoid Resistance in COPD, Severe Asthma and Smoking Asthma
Barnes PJ, J Steroid Biochem Mol Biol. 2010
Molecular Mechanisms of Steroid Resistance
• Defective histone acetylation– Reduced acetylation of lysine 5 on histone 4– Reduced histone deacetylase 2– Increased oxidative stress– Increased phosphoinositide-3-kinase-δ
activation• Increased P-glycoprotein
– Increased efflux of steroids
Barnes PJ, Adcock IA, Lancet 2009
(4m DNA nükleusta paketlenir50,000x kısaltılarak))
Nucleosomal Structure: DNA is wrapped around the histone octamer
Wolffe AP, Haynes J: Nucl Acids Res 1999
DNA
* =Acetylation sites: Lysine residues
H4 H4
H2B
H2A
H3 H3
**
***
* ***
***
**
**
*
*
*****
***** *M
P
M
M
M
M
R R
H2B
H2A P
(Courtesy of I Adcock)
Histone Acetylation(transcriptional activation)
Histone Acetyltransferase
Histone Deacetylation
(Gene silencing)
Histone Deacetylase
Histone acetylation/deacetylation controls gene expression
4 classes: HDAC 1 - 11sirtuins 1-7
P300/CBP, PCAF, TAFs, SRC-1, ACTR, TIP60
(Courtesy of I Adcock)
Histon deasetilazların (HDAC) sınıflandırılması
Abnormal Expression of HDACs in Airways Disease
Diseases with Abnormal HDAC Expression
• Asthma (smokers)• COPD• Others; rheumatoid arthritis, inflammatory
bowel disease • Adenocarcinoma patients with Cushing’
syndrome has low level of HDAC1
1Bilodeau S, et al, Genes Dev. 2006; Barnes PJ, Adcock IA, Lancet 2009
HAT activity
0
2500
5000
7500
N As-ICS
**
HAT a
ctiv
ity (
dpm
)
HDAC activity
0
50
100
150
HD
AC
act
ivit
y
(dpm
/mg
pro
tein
)
N As-ICS
**
As+ICS
#
As+ICS
#**
HAT and HDAC activity in asthmatic biopsies
r2 = 0.7803
p< 0.0001
0 100 200 30050
75
100
125
HDAC activity (dpm)
FE
V 1
(Courtesy of I. Adcock)Ito K, et al, AJRCCM. 2002
HDAC and HAT Expression in PBMCs of Normal and Asthmatic Individuals
Hew M, et al., AJRCCM 2006
HATHDAC
Relationship Between Endogenous HDAC and HAT Activities and BHR in Asthmatic Children
Su RC, et al,. JACI 2009
HAT and HDAC Activities in Peripheral Lung Tissue from Patients with COPD
HAT HDAC
KOAH evreKOAH evre
PN: PnumoniaCF: Cytstic fibrosis
Ito K, et al, NEJM. 2005
The Correlation Between HDAC Activity and FEV1/FVC
Ito K, et al, NEJM. 2005
HDAC Expression in Peripheral Lung Tissue.
HDAC 1-8 gene expression, real time PCR (* VS non-smoker and s0.)
GOLD Stage
Ito K, et al, NEJM. 2005
6 weeksTSAKontrol
Can We Enhance HDAC Activity and Restore ‘Normal’ Cell Function?
Cosio BG, et al, Am J Respir Crit Care 2004
Effect of Prednisolone on Activity and Expression of HDAC in PBMCs
(30 mg/daily 3-week treatment)
Activity and Expression of HDACs and HATs in BAL Macrophages
Cosio BG, et al, Am J Respir Crit Care 2004
HDAC HAT
Effect of Dexamethasone on Release of IL-8 and GM-CSF from Bronchial Epithelial Cells of COPD Patients
To Y, et al. Am J Respir Crit Care Med. 2010
Reversal of Corticosteroid Insensitivity by Theophylline in Smoking Mice
Effect of Theophylline on HDAC Activity and Dexamethasone Sensitivity in Alveolar Macrophages
(U937Hücreleri) Cosio BG, et al
J Exp Med. 2004
Change in Peak Expiratory Flow (PEF) Following 28 days of Treatment
Spears M, et al. Eur Respir J. 2009
Effect of FP+Low Dose Theophylline on HDAC Activity in PBMCs
post FP post FP & T0
250
500
750
1000
p < 0.01To
tal H
DA
C a
ctiv
ity
[rel
ativ
e lig
ht u
nits
]
Ford PA, et al. Chest 2010(Courtesy of I Adcock)
FP/Theo Improves Sputum Neutrophilia andLung Function
p=0.035
Pre Post0
25
50
75
100
Fluticasone & Theophylline
% N
eutr
ophi
ls
p=0.0239 (paired T-test)
Pre Post0
10
20
30
40
50
60
70
80
90
Fluticasone & Theophylline
FEV
1%
Ford PA, et al. Chest 2010(Courtesy of I Adcock)
Summary• Steroid resistance is an important problem• Histone acetylation and deacetylation is
important• The interventions to induce HDAC activity
(i.e. Theophylline) may contribute to the treatment
Thank You
