Proinflammatory Cytokines Impair Vitamin D–Induced Host Defense in Cultured Airway Epithelial Cells

Airway epithelial cells are the first line of defense against invading microbes, and they protect themselves through the production of carbohydrate and protein matrices concentrated with antimicrobial products. In addition, they act as sentinels, expressing pattern recognition receptors that become activated upon sensing bacterial products and stimulate downstream recruitment and activation of immune cells which clear invading microbes. Bacterial pathogens that successfully colonize the lungs must resist these mechanisms or inhibit their production, penetrate the epithelial barrier, and be prepared to resist a barrage of inflammation. Despite the enormous task at hand, relatively few virulence factors coordinate the battle with the epithelium while simultaneously providing resistance to inflammatory cells and causing injury to the lung. Here we review mechanisms whereby airway epithelial cells recognize pathogens and activate a program of antibacterial pathways to prevent colonization of the lung, along with a few examples of how bacteria disrupt these responses to cause pneumonia.

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Th1/17-Biased Inflammatory Environment Associated with COPD Alters the Response of Airway Epithelial Cells to Viral and Bacterial Stimuli

Mediators of Inflammation ◽

10.1155/2019/7281462 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Yifan Chen ◽

Rakesh K. Kumar ◽

Paul S. Thomas ◽

Cristan Herbert

Keyword(s):

Epithelial Cells ◽

Proinflammatory Cytokines ◽

Bacterial Infections ◽

Respiratory Infections ◽

Airway Epithelial Cells ◽

Poly I:C ◽

Chronic Obstructive ◽

Airway Epithelial ◽

Obstructive Pulmonary Disease ◽

Enhanced Expression

Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation associated with a Th1/17-biased cytokine environment. Acute exacerbations of COPD (AECOPD) are most often triggered by respiratory infections, which elicit an exaggerated inflammatory response in these patients, via poorly defined mechanisms. We investigated the responses of airway epithelial cells (AECs) to infective stimuli in COPD and the effects of the Th1/17-biased environment on these responses. Cytokine expression was assessed following exposure to virus-like stimuli (poly I:C or imiquimod) or bacterial LPS. The effects of pretreatment with Th1/17 cytokines were evaluated in both primary AECs and the Calu-3 AEC cell line. We found that poly I:C induced increased expression of the proinflammatory cytokines IL1β, IL6, CXCL8, and TNF and IFN-β1 in AECs from both control subjects and COPD patients. Expression of IL1β in response to all 3 stimuli was significantly enhanced in COPD AECs. Primary AECs pretreated with Th1/17 cytokines exhibited enhanced expression of mRNA for proinflammatory cytokines in response to poly I:C. Similarly, Calu-3 cells responded to virus-like/bacterial stimuli with increased expression of proinflammatory cytokines, and a Th1/17 environment significantly enhanced their expression. Furthermore, increased expression of pattern recognition receptors for viruses (TLR3, TLR7, IFIH1, and DDX58) was induced by Th1/17 cytokines, in both primary AECs and Calu-3 cells. These findings suggest that the Th1/17-biased environment associated with COPD may enhance the proinflammatory cytokine response of AECs to viral and bacterial infections and that increased signaling via upregulated receptors may contribute to exaggerated inflammation in virus-induced AECOPD.

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Activation of Vitamin D Regulates Response of Human Bronchial Epithelial Cells toAspergillus fumigatusin an Autocrine Fashion

Mediators of Inflammation ◽

10.1155/2015/208491 ◽

2015 ◽

Vol 2015 ◽

pp. 1-14 ◽

Cited By ~ 2

Author(s):

Pei Li ◽

Ting Wu ◽

Xin Su ◽

Yi Shi

Keyword(s):

Vitamin D ◽

Epithelial Cells ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Active Vitamin ◽

Human Airway ◽

Active Vitamin D ◽

Bidirectional Regulation ◽

The Impact ◽

Human Airway Epithelial Cells

Aspergillus fumigatus(A. fumigatus) is one of the most common fungi to cause diseases in humans. Recent evidence has demonstrated that airway epithelial cells play an important role in combatingA. fumigatusthrough inflammatory responses. Human airway epithelial cells have been proven to synthesize the active vitamin D, which plays a key role in regulating inflammation. The present study was conducted to investigate the impact ofA. fumigatusinfection on the activation of vitamin D and the role of vitamin D activation inA. fumigatus-elicited antifungal immunity in normal human airway epithelial cells. We found thatA. fumigatusswollen conidia (SC) induced the expression of 1α-hydroxylase, the enzyme catalyzing the synthesis of active vitamin D, and vitamin D receptor (VDR) in 16HBE cells and led to increased local generation of active vitamin D. Locally activated vitamin D amplified SC-induced expression of antimicrobial peptides in 16HBE cells but attenuated SC-induced production of cytokines in an autocrine fashion. Furthermore, we identifiedβ-glucan, the majorA. fumigatuscell wall component, as the causative agent for upregulation of 1α-hydroxylase and VDR in 16HBE cells. Therefore, activation of vitamin D is inducible and provides a bidirectional regulation of the responses toA. fumigatusin 16HBE cells.

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Impaired nitric oxide synthase-2 signaling pathway in cystic fibrosis airway epithelium

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00039.2004 ◽

2004 ◽

Vol 287 (2) ◽

pp. L374-L381 ◽

Cited By ~ 41

Author(s):

Shuo Zheng ◽

Weiling Xu ◽

Santanu Bose ◽

Amiya K. Banerjee ◽

S. Jaharul Haque ◽

...

Keyword(s):

Nitric Oxide ◽

Cystic Fibrosis ◽

Epithelial Cells ◽

Signaling Pathway ◽

Host Defense ◽

Airway Epithelial Cells ◽

Activator Protein 1 ◽

Airway Epithelial ◽

Ifn Γ ◽

Nos2 Expression

Cystic fibrosis (CF) airway epithelial cells are more susceptible to viral infection due to impairment of the innate host defense pathway of nitric oxide (NO). NO synthase-2 (NOS2) expression is absent, and signal transducer and activator of transcription (STAT) 1 activation is reduced in CF. We hypothesized that the IFN-γ signaling pathway, which leads to NOS2 gene induction in CF airway epithelial cells, is defective. In contrast to a lack of NOS2 induction, the major histocompatibility complex class 2, an IFN-γ-regulated delayed-responsive gene, is similarly induced in CF and non-CF airway epithelial (NL) cells, suggesting an NOS2-specific defect in the IFN-γ signaling pathway. STAT1 and activator protein-1, both required for NOS2 gene expression, interact normally in CF cells. Protein inhibitor of activated STAT1 is not increased in CF cells. IFN-γ induces NOS2 expression in airway epithelial cells through an autocrine mechanism involving synthesis and secretion of IFN-γ-inducible mediator(s), which activates STAT1. Here, CF cells secrete IFN-γ-inducible factor(s), which stimulate NOS2 expression in NL cells, but not in CF cells. In contrast, IFN-γ-inducible factor(s) similarly inhibit virus in CF and NL cells. Thus autocrine activation of NOS2 is defective in CF cells, but IFN-γ induction of antiviral host defense is intact.

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