Th1 cytokines TNF-α and IFN-γ promote corticosteroid resistance in developing human airway smooth muscle

Abstract

Corticosteroids (CSs) are commonly used to manage wheezing and asthma in pediatric populations. Although corticosteroids are effective in alleviating airway diseases, some children with more moderate-severe asthma phenotypes show CS resistance and exhibit significant airflow obstruction, persistent inflammation, and more frequent exacerbations. Previous studies have demonstrated that Th1 cytokines, such as TNF-α and IFN-γ, promote CS resistance in adult human airway smooth muscle (ASM). In the present study, using a human fetal ASM cell model, we tested the hypothesis that TNF-α/IFN-γ induces CS resistance. In contrast to TNF-α or IFN-γ alone, the combination of TNF-α/IFN-γ blunted the ability of fluticasone propionate (FP) to reduce expression of the chemokines CCL5 and CXCL10 despite expression of key anti-inflammatory glucocorticoid receptor target genes being largely unaffected by TNF-α/IFN-γ. Expression of the NF-κB subunit p65 and phosphorylation of Stat1 were elevated in cells treated with TNF-α/IFN-γ, an effect that remained in the presence of FP. siRNA knockdown studies demonstrated the effects of TNF-α/IFN-γ on increased p65 are mediated by Stat1, a transcription factor activated by IFN-γ. Expression of TNFAIP3, a negative regulator of NF-κB activity, was not altered by TNF-α/IFN-γ. However, the effects of TNF-α/IFN-γ were partially reduced by overexpression of TNFAIP3 but did not influence p65 expression. Together, these data suggest that IFN-γ augments the effects of TNF-α on chemokines by enhancing expression of key inflammatory pathways in the presence of CS. Interactions between TNF-α- and IFN-γ-mediated pathways may promote inflammation in asthmatic children resistant to CSs.

Ovalbumin-sensitized mice have altered airway inflammation to agriculture organic dust

“…In non-allergic asthma, neutrophil recruitment [34] and TNF-α [35] can result in AHR, but AHR can also occur independently of neutrophil recruitment or TNF [36]. Heightened Th1 inflammation with interactions between TNF-α and IFN-γ has also been shown to contribute to corticosteroid resistance in airway smooth muscle [37]. We speculate that combination and diversity of inflammatory mediators demonstrated in the co-exposure model contributes to the potentiated AHR.…”

Endotypes of Chronic Rhinosinusitis; relationships to disease phenotypes, pathogenesis, clinical findings and treatment approaches.

“…Neutrophils are relatively resistant to corticosteroid effects, however 146,147 . Reduced activity against T3 inflammation may explain the decreased corticosteroid responsiveness observed in clinical trials of Asian CRSwNP as well as CRSsNP in general versus Western CRSwNP 66,[147][148][149][150][151][152][153][154] . Topical corticosteroid sprays have limited access to inflamed sinus tissue but high-volume steroid irrigations, improved delivery devices and steroid-impregnated implants have improved efficacy [155][156][157][158][159][160] .…”

Why do some asthma patients respond poorly to glucocorticoid therapy?

“…Specifically, IFN-γ can increase GR phosphorylation and inhibit GR nuclear translocation in different experimental models of steroid-resistant airway hyperresponsiveness by up-regulating miR-9 expression in the lung and pulmonary macrophages [ 48 ]. Recently, TNF-α and IFN-γ cytokines have been shown to sustain glucocorticoid-resistance in human fetal airway smooth muscle cells by promoting the Nuclear factor-κB (NF-κB) pathway and Stat1 phosphorylation [ 49 ].…”