Abstract
BackgroundAlthough corticosteroid is a powerful anti-inflammatory drug that is used widely to control asthma, still severe asthmatics can develop steroid resistance. Airway fibroblasts are quite resistant to steroids during Idiopathic pulmonary fibrosis (IPF) and fibrosis in asthmatic lungs is not always controlled. Th-17 regulatory cytokine which are elevated in lung tissues of asthmatics were shown to enhance the survival of various types of cells. STAT factors are central to this anti-apoptotic function. However, it is not yet clear whether these cytokines contribute to steroid hypo-responsiveness in asthma. Therefore, in this study, we investigated the ability of Th-17 regulatory cytokines, specifically IL-21, IL22 and IL23, to protect structural airway cells against dexamethasone-induced apoptosis.MethodsPrimary human fibroblasts, ASM cells, and lung endothelial cells line were treated with IL-21, IL-22, and IL-23 cytokines before incubation with dexamethasone and the level of apoptosis was determined by measuring cellular Annexin-V using Flow cytometry.ResultsOur data indicated that treatment with Th-17 regulatory cytokines was effective in inhibiting induced apoptosis for both fibroblasts and endothelial cells but not ASM cells. STAT3 phosphorylation levels were also upregulated in fibroblasts and endothelial upon treatment with these cytokines. Interestingly, inhibiting STAT3 phosphorylation abrogated IL-21, IL-22, and IL-23 anti-apoptotic effect on fibroblasts and endothelial cells.ConclusionsThis data suggest that Th-17 regulatory cytokines may play a critical role in regulating the survival of fibroblasts during asthma, IPF as well as other chronic lung inflammatory diseases leading to enhanced fibrosis. Accordingly, findings of this paper may pave the way for more extensive research on the role of these regulatory cytokines in fibrosis development in various chronic inflammatory diseases.
Highlights
Corticosteroid is a powerful anti-inflammatory drug that is used widely to control asthma, still severe asthmatics can develop steroid resistance
IL-21, IL-22 and IL-23 cytokines protect endothelial cells and fibroblasts from dexamethasone induced apoptosis The frequency of Th-17 cells and the levels of their regulatory cytokines (IL-21, IL-23) as well as IL-22 were shown to be upregulated in inflamed lung tissues [32, 53, 54]
Prior stimulation with IL-21, IL-22 and IL-23 cytokines either alone or in combinations significantly protected the cells from dexamethasone induced apoptosis (Fig. 1; endothelial cells (IL-21: 9.4 %, IL-22: 8.2 %, IL-23:8.78 %, IL21 +IL-22: 8.25 %, IL-21+IL-23: 4.1 %, IL-22+IL-23: 5.5 %, IL-21+IL22+IL-23: 8.4 %; all p
Summary
Corticosteroid is a powerful anti-inflammatory drug that is used widely to control asthma, still severe asthmatics can develop steroid resistance. Airway fibroblasts are quite resistant to steroids during Idiopathic pulmonary fibrosis (IPF) and fibrosis in asthmatic lungs is not always controlled. STAT factors are central to this anti-apoptotic function It is not yet clear whether these cytokines contribute to steroid hypo-responsiveness in asthma. In this study, we investigated the ability of Th-17 regulatory cytokines, IL-21, IL22 and IL23, to protect structural airway cells against dexamethasone-induced apoptosis. In the airway tissues of asthmatics, improvement of the inflammatory state results, at least in part, from the glucocorticoid-induced. Even though glucocorticoid treatment helps to control airway inflammation, airway remodelling could be enhanced by high-doses or chronic (long-term) exposure to these drugs [6, 7]. Airway epithelium damage in asthmatics is promoted by glucocorticoid therapy, by inducing epithelial
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