Imperial College London
Alternate

ProfessorJonFriedland

Faculty of Medicine, Department of Infectious Disease

Visiting Professor
 
 
 
//

Contact

 

+44 (0)20 3313 8521j.friedland Website

 
 
//

Assistant

 

Ms Teyanna Gaeta +44 (0)20 3313 1943

 
//

Location

 

8N21ACommonwealth BuildingHammersmith Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Moores:2017:10.3389/fimmu.2017.00602,
author = {Moores, R and Dos, Santos Brilha S and Schutgens, F and Elkington, P and Friedland, JS},
doi = {10.3389/fimmu.2017.00602},
journal = {Frontiers in Immunology},
title = {Epigenetic regulation of Matrix metalloproteinase-1 and -3 expression in mycobacterium tuberculosis infection},
url = {http://dx.doi.org/10.3389/fimmu.2017.00602},
volume = {8},
year = {2017}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - In pulmonary tuberculosis (TB), the inflammatory immune response against Mycobacterium tuberculosis (Mtb) is associated with tissue destruction and cavitation, which drives disease transmission, chronic lung disease, and mortality. Matrix metalloproteinase (MMP)-1 is a host enzyme critical for the development of cavitation. MMP expression has been shown to be epigenetically regulated in other inflammatory diseases, but the importance of such mechanisms in Mtb-associated induction of MMP-1 is unknown. We investigated the role of changes in histone acetylation in Mtb-induced MMP expression using inhibitors of histone deacetylases (HDACs) and histone acetyltransferases (HAT), HDAC siRNA, promoter-reporter constructs, and chromatin immunoprecipitation assays. Mtb infection decreased Class I HDAC gene expression by over 50% in primary human monocyte-derived macrophages but not in normal human bronchial epithelial cells (NHBEs). Non-selective inhibition of HDAC activity decreased MMP-1/-3 expression by Mtb-stimulated macrophages and NHBEs, while class I HDAC inhibition increased MMP-1 secretion by Mtb-stimulated NHBEs. MMP-3 expression, but not MMP-1, was downregulated by siRNA silencing of HDAC1. Inhibition of HAT activity also significantly decreased MMP-1/-3 secretion by Mtb-infected macrophages. The MMP-1 promoter region between −2,001 and −2,942 base pairs from the transcriptional start site was key in control of Mtb-driven MMP-1 gene expression. Histone H3 and H4 acetylation and RNA Pol II binding in the MMP-1 promoter region were increased in stimulated NHBEs. In summary, epigenetic modification of histone acetylation via HDAC and HAT activity has a key regulatory role in Mtb-dependent gene expression and secretion of MMP-1 and -3, enzymes which drive human immunopathology. Manipulation of epigenetic regulatory mechanisms may have potential as a host-directed therapy to improve outcomes in the era of rising TB drug resistance.
AU  - Moores,R
AU  - Dos,Santos Brilha S
AU  - Schutgens,F
AU  - Elkington,P
AU  - Friedland,JS
DO  - 10.3389/fimmu.2017.00602
PY  - 2017///
SN  - 1664-3224
TI  - Epigenetic regulation of Matrix metalloproteinase-1 and -3 expression in mycobacterium tuberculosis infection
T2  - Frontiers in Immunology
UR  - http://dx.doi.org/10.3389/fimmu.2017.00602
UR  - http://hdl.handle.net/10044/1/48480
VL  - 8
ER  -
Download