Glucocorticoid actions on airway epithelial responses in immunity: Functional outcomes and molecular targets

Stellato, Cristiana

doi:10.1016/j.jaci.2007.10.041

Cited by 50 publications

(49 citation statements)

References 167 publications

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“…Both HC and FP robustly induced PLZF, MKP-1, and CDKN1C mRNA in a concentration-dependent manner. Transactivation of these genes is considered important in facilitating GC antiinflammatory and antiproliferative actions in various types of cells (19,38,39). We observed distinct lower maxima to HC compared with FP in inducing these targets.…”

Section: Discussionmentioning

confidence: 57%

Cortisol limits selected actions of synthetic glucocorticoids in the airway epithelium

et al. 2018

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Cortisol, a physiologic glucocorticoid (GC), is essential for growth and differentiation of the airway epithelium. Epithelial function influences inflammation in chronic respiratory diseases. Synthetic GCs, including inhaled corticosteroids, exert anti-inflammatory effects in airway epithelium by transactivation of genes and by inhibition of proinflammatory cytokine release. We examined the effect of cortisol on the actions of synthetic GCs in the airway epithelium, demonstrating that cortisol acts like a partial agonist at the GC receptor (GR), limiting GCinduced GR-dependent transcription in the BEAS-2B human bronchial epithelial cell line. Cortisol also limited the inhibition of granulocyte macrophage colony-stimulating factor release by synthetic GCs in TNF-a-activated BEAS-2B cells. The relevance of these findings is supported by observations on tracheal epithelium obtained from mice treated for 5 d with systemic GC, showing limitations in selected GC effects, including inhibition of IL-6. Moreover, gene transactivation by synthetic GCs was compromised by standard air-liquid interface (ALI) growth medium cortisol concentration (1.4 mM) in the ALI-differentiated organotypic culture of primary human airway epithelial cells. These findings suggest that endogenous corticosteroids may limit certain actions of synthetic pharmacological GCs and contribute to GC insensitivity, particularly when corticosteroid levels are elevated by

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Section: Discussionmentioning

confidence: 57%

Cortisol limits selected actions of synthetic glucocorticoids in the airway epithelium

et al. 2018

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“…The repression of inflammatory gene transcription by glucocorticoids is generally attributed to the action of glucocorticoids on proinflammatory transcription factors, such as NF-kB and AP-1 (46). Using Western blotting, EMSAs, and luciferase promoter constructs, we report that formoterol and dexamethasone do not modulate NF-kB activation, DNA binding, or transactivation.…”

Section: Discussionmentioning

confidence: 86%

Rhinovirus-Induced MMP-9 Expression Is Dependent on Fra-1, Which Is Modulated by Formoterol and Dexamethasone

Tacon

Newton

Leigh

2012

The Journal of Immunology

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Matrix metalloproteinase-9 is implicated in airway inflammation and airway remodeling in asthma. We have previously confirmed that human rhinovirus-16 (HRV-16) infection increases MMP-9 expression both in vivo and in vitro. However, the role of the AP-1 sites within the MMP-9 promoter and the effect of commonly used asthma pharmacotherapies in modulating human rhinovirus (HRV)-induced MMP-9 production have not yet been elucidated. Experiments were performed in vitro in the human bronchial epithelial (HBE) cell line BEAS-2B and in primary HBE cells obtained from non-transplanted lungs. Using site-directed mutagenesis approaches, AP-1 sites were found to be necessary for HRV-induced MMP-9 promoter drive. EMSAs and supershift assays identified complexes consisting of Fos-related Ag-1 (Fra-1) in addition to other AP-1 subunits. Small interfering RNA approaches indicated that Fra-1 was induced upon HRV-16 infection in BEAS-2B cells and was necessary for MMP-9 expression in both BEAS-2B and primary HBE cells. Inhibition of MEK1/2 activity using PD98059 and U0126 reduced Fra-1 expression, DNA binding, MMP-9 promoter drive, and MMP-9 protein production. The long-acting β2-agonist formoterol and the glucocorticoid dexamethasone significantly reduced HRV-induced ERK phosphorylation, Fra-1, and MMP-9 expression in BEAS-2B cells. These data indicate that HRV-induced activation of the MEK/ERK MAPK pathway and Fra-1 expression are necessary for the upregulation of MMP-9 and can be modulated by two distinct but commonly used asthma pharmacotherapies. Together, these results offer insights into the mechanisms by which long-acting β2-agonists and glucocorticoids might reduce HRV-related asthma exacerbations.

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“…First, inhaled corticosteroids have profound effects on the airway epithelium, which normally facilitates adaptive immune responses by the synthesis of a wide array of lipid mediators, cytokines and chemokines. Central among the anti-inflammatory properties of corticosteroids is the ability to blunt the infiltration of inflammatory cells, including B-and T-cells, within the airways and lungs through the potent suppression of epithelial-derived cytokines and chemoattractants [70] ( fig. 3).…”

Section: Influence Of Pharmacotherapy On Lymphoid Folliclesmentioning

confidence: 99%

Lymphoid follicles in (very) severe COPD: beneficial or harmful?

Demoor

Bracke

Brandsma

et al. 2009

European Respiratory Journal

118

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Inflammation is a main pathogenetic factor in the development and progression of chronic obstructive pulmonary disease (COPD). Recently, it has become clear that not only the innate, but also the specific immune response plays a role. A striking finding, in particular in lungs of patients with severe COPD, often with a predominant emphysema phenotype, is the presence of B-cell follicles. As seen in other tissues, these follicles are the result of lymphoid neogenesis. The finding of oligoclonality in B-cell follicles in COPD suggests that they play a role in local antigen specific immune responses. To date, it is not known which antigens may be involved; microbial antigens, cigarette smoke-derived antigens and antigens from extracellular matrix breakdown products have been suggested. Consequently, the pathogenetic role of this follicular B-cell response is not yet clear. It might be protective against microbial colonisation and infection of the lower respiratory tract and, therefore, beneficial, or it could be of a more harmful (autoimmune) nature, directed against lung tissue components. It is necessary to determine the specific antigen(s) and to explore the exact role of the COPD related B-cell response in order to include modulation of this response and develop therapeutic options.

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Glucocorticoid actions on airway epithelial responses in immunity: Functional outcomes and molecular targets

Cited by 50 publications

References 167 publications

Cortisol limits selected actions of synthetic glucocorticoids in the airway epithelium

Cortisol limits selected actions of synthetic glucocorticoids in the airway epithelium

Rhinovirus-Induced MMP-9 Expression Is Dependent on Fra-1, Which Is Modulated by Formoterol and Dexamethasone

Lymphoid follicles in (very) severe COPD: beneficial or harmful?

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