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

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

In an in vitro model of human tuberculosis, monocyte-microglial networks regulate matrix metalloproteinase-1 and -3 gene expression and secretion via a p38 mitogen activated protein kinase-dependent pathway.

BACKGROUND: Tuberculosis (TB) of the central nervous system (CNS) is characterized by extensive tissue inflammation, driven by molecules that cleave extracellular matrix such as matrix metalloproteinase (MMP)-1 and MMP-3. However, relatively little is known about the regulation of these MMPs in the CNS. METHODS: Using a cellular model of CNS TB, we stimulated a human microglial cell line (CHME3) with conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb). MMP-1 and MMP-3 secretion was detected using ELISAs confirmed with casein zymography or western blotting. Key results of a phospho-array profile that detects a wide range of kinase activity were confirmed with phospho-Western blotting. Chemical inhibition (SB203580) of microglial cells allowed investigation of expression and secretion of MMP-1 and MMP-3. Finally we used promoter reporter assays employing full length and MMP-3 promoter deletion constructs. Student's t-test was used for comparison of continuous variables and multiple intervention experiments were compared by one-way ANOVA with Tukey's correction for multiple pairwise comparisons. RESULTS: CoMTb up-regulated microglial MMP-1 and MMP-3 secretion in a dose- and time-dependent manner. The phospho-array profiling showed that the major increase in kinase activity due to CoMTb stimulation was in p38 mitogen activated protein kinase (MAPK), principally the α and γ subunits. p38 phosphorylation was detected at 15 minutes, with a second peak of activity at 120 minutes. High basal extracellular signal-regulated kinase activity was further increased by CoMTb. Secretion and expression of MMP-1 and MMP-3 were both p38 dependent. CoMTb stimulation of full length and MMP-3 promoter deletion constructs demonstrated up-regulation of activity in the wild type but a suppression site between -2183 and -1612 bp. CONCLUSIONS: Monocyte-microglial network-dependent MMP-1 and MMP-3 gene expression and secretion are dependent upon p38 MAPK in tuberculosis. p38 is therefore a potential target for adjuvant therapy in CNS TB

Insects and disease

Dr. Elkington said:—The subject upon which I have been asked to address you this evening is one which has, within the past six years, produced a profound alteration in several branches of science. It is advisable, therefore, to clearly distinguish between the two methods in which insects play a part in spreading disease amongst human beings in relation to typhoid fever, whether (a) As carrying agents pure and simple, the infecting agent undergoing no change and not being dependent on the insect in any way. (b) As hosts, intermediate or definitive, the infective organism being dependent upon the insect and undergoing an extracorporeal phase of development in its tissues. Dr. Elkington believes that domestic flies are responsible for a large proportion of cases of disease, especially typhoid fever

O Kualoa, O Na Kanawai No Ia O Ko Mau Kupuna: Reviving Buried Ideas of ʻĀina Through Moʻolelo, Moʻokūʻauhau, and Aloha ʻĀina

M.A.M.A. Thesis. University of Hawaiʻi at Mānoa 201

Morphology, patterns and processes in the Oyster Bay headland bypass dunefield, South Africa

Studies of the dunefield systems crossing the Cape St. Francis headland in the Eastern Cape have focused on the role that wind plays in sediment transfer in coastal dunefield systems, with limited consideration of the role of water. The aim of this study was to improve understanding of the morphology, processes and patterns within the Oyster Bay HBD system, focussing particularly on surface water and groundwater interactions and the role of surface water in sediment transfer across the dunefield system. An extensive field survey was conducted, to collect related data, complimented by spatial and temporal analysis of the study area using GIS. The key findings from this research were the apparent differences between the western and eastern regions of the dunefield with regard to specific drivers and the respective processes and responses. Wind is the major driver of change up to and across the crest of the dunefield. In the eastern region water (ground water, surface water and the Sand River System) is the primary agent of sediment flux through processes of aggregation and slumping as well as episodic events including debris flows. This study has highlighted a need for further quantitative studies that investigate the movement of sediment through dunefield systems such as this (where water is at or near the land surface). The paradigm that sediment flux is entirely due to wind is almost certainly simplistic, and deeper understanding of these systems is needed

UTS Conference on Cosmopolitan Civil Societies

What does cosmopolitanism mean in an age where globalisation is accompanied by the War on Terror, and where unprecedented levels of international migration are accompanied by attacks on multiculturalism and heightened ‘border security’ politics