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Interleukin-17 regulates matrix metalloproteinase activity in human pulmonary tuberculosis.

Singh, S; Maniakis-Grivas, G; Singh, UK; Asher, RM; Mauri, F; Elkington, PT; Friedland, JS (2018) Interleukin-17 regulates matrix metalloproteinase activity in human pulmonary tuberculosis. J Pathol, 244 (3). pp. 311-322. ISSN 1096-9896 https://doi.org/10.1002/path.5013
SGUL Authors: Friedland, Jonathan Samuel

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Abstract

Tuberculosis (TB) is characterized 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 were 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 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 IL-23, were significantly up-regulated in BALF from TB patients. IL-17-driven MMP-3 was dependent on p38 MAP kinase and the PI3K 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 PI3K pathways. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Item Type: Article
Additional Information: © 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 (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: MMP, TH-17, immunopathology, innate immunity, mycobacteria, mycobacteria, MMP, innate immunity, T-H-17, immunopathology, Science & Technology, Life Sciences & Biomedicine, Oncology, Pathology, mycobacteria, MMP, innate immunity, T-H-17, immunopathology, NF-KAPPA-B, BRONCHIAL EPITHELIAL-CELLS, MYCOBACTERIUM-TUBERCULOSIS, P38 MAPK, MMP-1 EXPRESSION, IMMUNE-RESPONSE, TH17 CELLS, IL-17, ACTIVATION, SECRETION, 1103 Clinical Sciences, Pathology
Journal or Publication Title: J Pathol
ISSN: 1096-9896
Language: eng
Dates:
DateEvent
March 2018Published
18 January 2018Published Online
24 November 2017Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
UNSPECIFIEDMedical Research Councilhttp://dx.doi.org/10.13039/501100000265
UNSPECIFIEDNational Institute for Health Researchhttp://dx.doi.org/10.13039/501100000272
PubMed ID: 29210073
Web of Science ID: WOS:000425116400007
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/110636
Publisher's version: https://doi.org/10.1002/path.5013

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