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Corynebacterium tuberculostearicum, a human skin colonizer, induces the canonical nuclear factor-?B inflammatory signaling pathway in human skin cells.

ABSTRACT: INTRODUCTION:Corynebacterium tuberculostearicum (C. t.) is a ubiquitous bacterium that colonizes human skin. In contrast to other members of the genus Corynebacterium, such as toxigenic Corynebacterium diphtheriae or the opportunistic pathogen Corynebacterium jeikeium, several studies suggest that C. t. may play a role in skin health and disease. However, the mechanisms underlying these effects remain poorly understood. METHODS:To investigate whether C. t. induces inflammatory pathways in primary human epidermal keratinocytes (HEKs) and human cutaneous squamous carcinoma cells (SCCs), cell culture, reverse transcription-polymerase chain reaction (PCR), enzyme-linked immunosorbent assay, immunofluorescence microscopy, Western blot, chromatin immunoprecipitation-PCR, small interfering RNA knockdown and luciferase reporter expression system were used. RESULTS:Herein, we demonstrate that C. t. upregulates the messenger RNA (mRNA) and protein levels of inflammatory mediators in two human skin cell lines, HEKs and SCCs. We further show activation of the canonical nuclear factor-?B (NF-?B) pathway in response to C. t. infection, including phosphorylation of the inhibitor of ?B (I?B), the nuclear translocation of NF-?B subunit (NF-?B-P65 ) and the recruitment of NF-?B-P65 and RNA polymerase to the NF-?B response elements at the promoter region of the inflammatory genes. Lastly, the data confirm that C. t.-induced tumor necrosis factor mRNA expression in HEKs is toll-like receptor 2 (TLR2 ) dependent. CONCLUSION:Our results offer a mechanistic model for C. t.-induced inflammation in human keratinocytes via TLR2 and activation of I?B kinase and downstream signaling through the canonical NF-?B pathway. Relevance to chronic inflammatory diseases of the skin and cutaneous oncology is discussed.

SUBMITTER: Altonsy MO

PROVIDER: S-EPMC7016847 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Corynebacterium tuberculostearicum, a human skin colonizer, induces the canonical nuclear factor-κB inflammatory signaling pathway in human skin cells.

Altonsy Mohammed O MO Kurwa Habib A HA Lauzon Gilles J GJ Amrein Matthias M Gerber Anthony N AN Almishri Wagdi W Mydlarski Paule Régine PR

Immunity, inflammation and disease 20200107 1

<h4>Introduction</h4>Corynebacterium tuberculostearicum (C. t.) is a ubiquitous bacterium that colonizes human skin. In contrast to other members of the genus Corynebacterium, such as toxigenic Corynebacterium diphtheriae or the opportunistic pathogen Corynebacterium jeikeium, several studies suggest that C. t. may play a role in skin health and disease. However, the mechanisms underlying these effects remain poorly understood.<h4>Methods</h4>To investigate whether C. t. induces inflammatory pat ...[more]

PMID: 31912662

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Project description:The mechanisms of diabetic retinopathy (DR), are not yet fully understood. We previously demonstrated an upregulation of retinal bone morphogenetic protein-2 (BMP2) in experimental diabetes and in retinas of diabetic human subjects. The purpose of current study was to investigate the role of non-canonical inflammatory pathway in BMP2-induced retinal endothelial cell (REC) barrier dysfunction. For this purpose, we used RT-PCR and western blotting to evaluate the levels of BMP2 signaling components (BMP2, BMP4, BMP receptors), VEGF, phosphorylated p38 MAPK and NFκB, and oxidative stress markers in cultured human retinal endothelial cells (HRECs) subjected to BMP2 (50ng/ml) for up to 24 h. Also, effect of high glucose (HG, 30mM D-glucose) on the expression of BMP2 and its downstream genes was examined in HRECs. H2-DCF is a fluorogenic dye that measures the levels of cellular reactive oxygen species (ROS) was used to measure the pro-oxidative effect of BMP2. Moreover, we evaluated the effect of inhibiting p38 and VEGF signaling on BMP2-induced HRECs barrier dysfunction by measuring the trans-endothelial cell electrical resistance (TER) using electric cell-substrate impedance sensing (ECIS). We also tested the effect of HG on the integrity of HRECs barrier in the presence or absence of inhibitors of BMP2 signaling. Our data reveals that BMP2 and high glucose upregulates BMP components of the BMP signaling pathway (SMAD effectors, BMP receptors, and TGFβ ligand itself) and induces phosphorylation of p38 MAPK and NFκB with nuclear translocation of NFκB. Inhibition of p38 or NFκB attenuated BMP2-induced VEGF expression and barrier dysfunction in HRECs. Also, inhibition of VEGFR2 attenuated BMP2-induced barrier dysfunction. Moreover, BMP2 induces generation of ROS and endothelial nitric oxide synthase (eNOS) expression and activity in HRECs. Finally, HG upregulated BMP2 and its downstream genes (SMAD, BMP4, ALKs, and TGF-β) in HRECs and BMP2 inhibitors attenuated HG-induced HRECs barrier dysfunction. Our results suggest that in addition to the regular canonical SMAD signaling BMP2 induces non-canonical inflammatory pathway in HRECs via activation of p38/NFκB pathway that causes the upregulation of VEGF and the disruption of HRECs. Inhibition of BMP2 signaling is a potential therapeutic intervention to preserve endothelial cell barrier function in DR.

Dataset Information

Corynebacterium tuberculostearicum, a human skin colonizer, induces the canonical nuclear factor-?B inflammatory signaling pathway in human skin cells.

Publications

Corynebacterium tuberculostearicum, a human skin colonizer, induces the canonical nuclear factor-κB inflammatory signaling pathway in human skin cells.

Similar Datasets

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