Interleukin-17 regulates matrix metalloproteinase activity in human pulmonary tuberculosis
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Tuberculosis (TB) is characterised by extensive pulmonary matrix breakdown. Interleukin-17 (IL-17) is key in host defence in TB but its role in TB-driven tissue damage is unknown. We investigated the hypothesis that respiratory stromal cell matrix metalloproteinase (MMP) production in TB is regulated by T helper-17 (TH-17) cytokines. Biopsies of patients with pulmonary TB were analysed by immunohistochemistry (IHC) and patient bronchoalveolar lavage fluid (BALF) MMP and cytokine concentrations measured by Luminex assays. Primary human airway epithelial cells were stimulated with conditioned medium from human monocytes infected with Mycobacterium tuberculosis (Mtb) and TH-17 cytokines. MMP secretion, activity and gene expression were determined by ELISA, Luminex assay, zymography, RT-qPCR and dual luciferase reporter assays. Signalling pathways were examined using phospho-western analysis and siRNA. IL-17 is expressed in TB patient granulomas and MMP-3 is expressed in adjacent pulmonary epithelial cells. IL-17 had a divergent, concentration-dependent effect on MMP secretion, increasing epithelial secretion of MMP-3 (p<0.001) over 72 h whilst decreasing that of MMP-9 (p<0.0001); mRNA levels were similarly affected. Both IL-17 and Interleukin-22 (IL-22) increased fibroblast Mtb-dependent MMP-3 secretion but IL-22 did not modulate epithelial MMP-3 expression. Both IL-17 and IL-22, but not Interleukin-23 (IL-23), were significantly upregulated in BALF from TB patients. IL-17-driven MMP-3 was dependent on p38 MAP kinase and the PI 3-K p110α subunit. In summary, IL-17 drives airway stromal cell-derived MMP-3, a mediator of tissue destruction in TB, alone and with monocyte-dependent networks in TB. This is regulated by p38 MAP kinase and PI3-K pathways.
Date Issued
2018-01-18
Date Acceptance
2017-11-24
Citation
Journal of Pathology, 2018, 244 (3), pp.311-322
ISSN
0022-3417
Publisher
Wiley
Start Page
311
End Page
322
Journal / Book Title
Journal of Pathology
Volume
244
Issue
3
Copyright Statement
© 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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Subjects
MMP
TH-17
immunopathology
innate immunity
mycobacteria
1103 Clinical Sciences
Pathology
Publication Status
Published