Effect of inhaled beclomethasone dipropionate on expression of proinflammatory cytokines and activated eosinophils in the bronchial epithelium of patients with mild asthma

Wang, Jia Hua; Trigg, C.J.; Devalia, Jagdish L.; Jordan, S.; Davies, Robert J.

doi:10.1016/0091-6749(94)90121-x

Cited by 80 publications

(37 citation statements)

References 30 publications

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“…IL-8 also augments the production ofproteases by neutrophils (56), generation of oxygen radi-cals (57), and activity of 5-1ipoxygenase in PMN cells (58). Our data obtained in vitro are consistent with the clinical observation of elevated levels of IL-6 and IL-8 in the bronchoalveolar lavages and biopsies of symptomatic asthmatic individuals (59,60).…”

supporting

confidence: 79%

Platelet-activating factor exerts mitogenic activity and stimulates expression of interleukin 6 and interleukin 8 in human lung fibroblasts via binding to its functional receptor.

Roth

Nauck

Yousefi

et al. 1996

The Journal of Experimental Medicine

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SummaryPlatelet-activating factor (PAF) is a potent proinflammatory phosphohpid mediator of the lung. In this study, we demonstrate that PAF receptor mRNA and protein is expressed by human lung fibroblasts. Interaction of PAF with its specific receptor resulted in increases of tyrosine phosphorylation of several intracellular proteins, indicating that the PAF-receptor might be functionally active. PAF-induced transcription ofprotooncogenes c-fos and c-jun as well as of interleukin (IL)-6 and IL-8 genes in human fibroblasts. Transcription of the interleukins was followed by secretion of the respective proteins. Moreover, PAF enhanced proliferation of fibroblasts in a concentration-dependent manner. Using signaling inhibitors, we demonstrate that PAF-induced transcription of the c-fos, IL-6, and IL-8 genes, as well as proliferation, require activation of pertussis toxin-sensitive G proteins, tyrosine kinases, and protein kinase C (PKC). In contrast, transcription of c-jun was blocked by pertussis toxin, but not by inhibitors for tyrosine kinases or PKC. These data suggest that PAF stimulates distinct signahng pathways in human lung fibroblasts. In addition, the activation of human fibroblasts by PAF leads to enhanced proliferation and to the expression of proinflammatory cytokines, which may contribute to the pathophysiological changes in pulmonary inflammation.

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supporting

confidence: 79%

Platelet-activating factor exerts mitogenic activity and stimulates expression of interleukin 6 and interleukin 8 in human lung fibroblasts via binding to its functional receptor.

Roth

Nauck

Yousefi

et al. 1996

The Journal of Experimental Medicine

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“…Overall, the finding that H. influenzae endotoxin induced significant release of IL-6, IL-8 and TNF-α and increased the expression of ICAM-1 in human bronchial epithelial cell cultures may be of particular importance in bacterial-induced airway inflammation, since these mediators have been shown to exert a significant influence on neutrophil activity [32,35,37]. Additionally, since H. influenzae endotoxin was not shown to affect the synthesis and release of epithelial GM-CSF or RANTES, which influence primarily the activity of eosinophils [59,60], these studies suggest that the effects of endotoxin are likely to be selective and directed towards synthesis and release of mediators that increase neutrophil recruitment and infiltration of the airways. Since endotoxin from type b H. influenzae was also shown to lead to a much greater release of IL-8 and TNF-α than endotoxin from the nontypable strain of H. influenzae, this may be of particular significance and could explain the differences in the pathogenicity of the two strains.…”

Section: Allergen Air Pollutantsmentioning

confidence: 99%

Bacterial-induced release of inflammatory mediators by bronchial epithelial cells

Khair¹,

Davies²,

Devalia³

1996

Eur Respir J

165

118

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“…Among the soluble factors evoked by IL-4/13 stimulation under these conditions, of particular interest are granulocyte/macrophage colony-stimulating factor (GM-CSF) and transforming growth factor (TGF)-␤ 2 (17,20,24,31). These factors are of special interest because of their purported role in the biology of asthma (22,27) and AHR (11,30).We investigated signal transducer and activator of transcription (STAT)6 phosphorylation and secretion of GM-CSF and TGF-␤ 2 in airway epithelial cells grown using the two most commonly employed culture techniques, monolayer submerged cultures on plastic and ALI cultures on microporous substrates, to identify the dependence of IL-4/13-induced signal transduction and soluble protein secretion on the culture technique employed. Our results indicate that, although early signal transduction responses to IL-4/13 stimulation such as STAT6 phosphorylation may be independent of the culture conditions employed, the transduction of these early responses into downstream responses such as GM-CSF and TGF-␤ 2 secretion may depend strongly on the culture technique and the resulting polarity and differentiation status of the cultures.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Differentiation-dependent responsiveness of bronchial epithelial cells to IL-4/13 stimulation

Kikuchi¹,

Shively²,

Foley³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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/ajplung.00365.2003.-The Th2 cytokines interleukin (IL)-4 and IL-13 are thought to play critical roles in the airway inflammation and hyperresposiveness that characterize asthma. Recent evidence indicates that IL-13 can mediate these effects by acting directly on airway epithelial cells. Here we evaluated early [signal transducer and activator of transcription (STAT)6 phosphorylation] and delayed [granulocyte/macrophage colony-stimulating factor (GM-CSF) and transforming growth factor-␤ 2 (TGF-␤2) secretion] responses of airway epithelial cells to IL-4 and IL-13 stimulation and the dependence of these responses on the culture technique employed. As expected, normal human bronchial epithelial cells grown on microporous inserts at an air-liquid interface (ALI) expressed a well-differentiated mucociliary phenotype; in contrast, cells grown on plastic in submerged cultures were poorly differentiated. When stimulated with IL-4 or IL-13, the magnitude and duration of STAT6 phosphorylation under the differing culture conditions were statistically indistinguishable. In contrast, cytokine secretion responses to IL-4 and IL-13 were highly dependent on the culture technique; cells cultured on plastic exhibited significant concentration-dependent increases in GM-CSF and TGF-␤ 2 secretion, whereas cells grown at ALI showed no statistically significant response. These results demonstrate that the coupling between early signal transduction responses to IL-4 and IL-13 and downstream functions such as cytokine secretion may be critically dependent on the cell culture technique employed and the resulting differentiation status of bronchial epithelial cells.bronchial epithelial cells; cell differentiation; interleukin-4/13; granulocyte/macrophage colony-stimulating factor; transforming growth factor-␤ THE TH2 CYTOKINES interleukin (IL)-4 and IL-13 have been shown to play critical roles in allergic inflammation and the development of airway hyperresponsiveness (AHR; see Ref. 32). Although both cytokines play key roles in T-cell phenotypic commitment and IgE production (32, 34), recent evidence demonstrates that IL-13 can mediate the development of AHR by direct action on airway epithelial cells (13). These results underscore the need to understand the gene and protein responses evoked in the airway epithelium by IL-4 and, especially, IL-13.In vivo, the airway epithelium is composed of a mixed population of ciliated, nonciliated, and mucous-secreting cells (10). Studies using bronchial epithelial cell cultures differentiated to induce a mucociliary phenotype have shown that IL-4 and IL-13 stimulation modulate basic cell functions such as proliferation (3), ciliary beating, and mucous production (2, 14, 25). In contrast, our growing understanding of the ability of Th2 cytokines to stimulate gene expression (15) and production of soluble factors (4,17,20,24,31) is derived primarily from study of submerged cultures of airway epithelial cells grown on plastic, conditions that result in a poorly differentiated, proliferating cell popula...

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Effect of inhaled beclomethasone dipropionate on expression of proinflammatory cytokines and activated eosinophils in the bronchial epithelium of patients with mild asthma

Cited by 80 publications

References 30 publications

Platelet-activating factor exerts mitogenic activity and stimulates expression of interleukin 6 and interleukin 8 in human lung fibroblasts via binding to its functional receptor.

Platelet-activating factor exerts mitogenic activity and stimulates expression of interleukin 6 and interleukin 8 in human lung fibroblasts via binding to its functional receptor.

Bacterial-induced release of inflammatory mediators by bronchial epithelial cells

Differentiation-dependent responsiveness of bronchial epithelial cells to IL-4/13 stimulation

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