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ESAT-6 Drives MMP-10 Gene Expression and Secretion in Tuberculosis.

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Title: ESAT-6 Drives MMP-10 Gene Expression and Secretion in Tuberculosis.
Authors: Brilha, S
Sathyamoorthy, T
Stuttaford, LH
Walker, NF
Wilkinson, RJ
Singh, S
Moores, RC
Elkington, PT
Friedland, JS
Item Type: Journal Article
Abstract: Tuberculosis (TB) causes disease worldwide and multi-drug resistance is an increasing problem. Matrix metalloproteinases (MMPs), particularly the collagenase MMP-1, cause lung extracellular matrix destruction which drives disease transmission and morbidity. The role in such tissue damage of the stromelysin MMP-10, a key activator of the collagenase MMP-1, was investigated in direct Mycobacterium tuberculosis (Mtb) infected macrophages and in conditioned medium from Mtb infected monocytes (CoMtb)-stimulated cells. Mtb infection increased MMP-10 secretion from primary human macrophages 29-fold, while CoMtb increased secretion by 4.5-fold from pulmonary epithelial cells and 10.5-fold from fibroblasts. Inhibition of MMP-10 activity decreased collagen breakdown. In two independent cohorts of TB patients from different continents, MMP-10 was increased in both induced sputum and bronchoalveolar lavage fluid compared to controls and patients with other respiratory diseases (both p<0.05). Mtb drove 3.5-fold greater MMP-10 secretion from human macrophages than the vaccine strain BCG (p<0.001), whereas both mycobacteria upregulated TNFα secretion equally. Using overlapping short linear peptides covering the sequence of ESAT-6, a virulence factor secreted by Mtb but not BCG, we found that stimulation of human macrophages with a single specific 15 amino acid peptide sequence drove 3-fold greater MMP-10 secretion than any other peptide (p<0.001). Mtb-driven MMP-10 secretion was inhibited in a dose-dependent manner by p38 and ERK MAPK blockade (p<0.001 and p<0.01 respectively), but was not affected by inhibition of NF-ĸB. In summary, Mtb activates inflammatory and stromal cells to secrete MMP-10 and this is partly driven by the virulence factor ESAT-6, implicating it in TB-associated tissue destruction.
Issue Date: 21-Sep-2016
Date of Acceptance: 20-Sep-2016
URI: http://hdl.handle.net/10044/1/41093
DOI: https://dx.doi.org/10.1165/rcmb.2016-0162OC
ISSN: 1535-4989
Publisher: American Thoracic Society
Start Page: 223
End Page: 232
Journal / Book Title: American Journal of Respiratory Cell and Molecular Biology
Volume: 56
Issue: 2
Copyright Statement: Copyright © 2016 by the American Thoracic Society
Sponsor/Funder: Medical Research Council (MRC)
Wellcome Trust
Medical Research Council
Portuguese Foundation for Science and Technology
Rosetrees Trust / Leicester Foundation
Funder's Grant Number: G0900429
094000/Z/10/Z
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Respiratory System
matrix metalloproteinases
early secretory antigenic target-6
tuberculosis
NF-KAPPA-B
MYCOBACTERIUM-TUBERCULOSIS
PULMONARY TUBERCULOSIS
P38 MAPK
CALMETTE-GUERIN
ACTIVATION
INFECTION
MMP-10
DISEASE
PROTEIN
Amino Acid Sequence
Antigens, Bacterial
Bacterial Proteins
Epithelial Cells
Fibroblasts
Gene Expression Regulation, Enzymologic
Humans
Lung
Macrophages
Matrix Metalloproteinase 1
Matrix Metalloproteinase 10
Mitogen-Activated Protein Kinases
Mycobacterium tuberculosis
NF-kappa B
Tuberculosis
Tuberculosis Vaccines
Virulence
ESAT-6
Matrix Metalloproteinases
1102 Cardiovascular Medicine And Haematology
Publication Status: Published
Appears in Collections:Department of Medicine
Faculty of Medicine



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