Thiazolidinediones inhibit airway smooth muscle release of the chemokine CXCL10: in vitro comparison with current asthma therapies

Abstract

BackgroundActivated mast cells are present within airway smooth muscle (ASM) bundles in eosinophilic asthma. ASM production of the chemokine CXCL10 plays a role in their recruitment. Thus the effects of glucocorticoids (fluticasone, budesonide), long-acting β2-agonists (salmeterol, formoterol) and thiazolidinediones (ciglitazone, rosiglitazone) on CXCL10 production by ASM cells (ASMC) from people with and without asthma were investigated in vitro.MethodsConfluent serum-deprived cells were treated with the agents before and during cytokine stimulation for 0-24 h. CXCL10 protein/mRNA, IκB-α levels and p65 activity were measured using ELISA, RT PCR, immunoblotting and p65 activity assays respectively. Data were analysed using ANOVA followed by Fisher’s post-hoc test.ResultsFluticasone and/or salmeterol at 1 and 100 nM inhibited CXCL10 release induced by IL-1β and TNF-α, but not IFNγ or all three cytokines (cytomix). The latter was also not affected by budesonide and formoterol. In asthmatic ASMC low salmeterol, but not formoterol, concentrations increased cytomix-induced CXCL10 release and at 0.01 nM enhanced NF-κB activity. Salmeterol 0.1nM together with fluticasone 0.1 and 10 nM still increased CXCL10 release. The thiazolidinediones ciglitazone and rosiglitazone (at 25 and 100 μM) inhibited cytomix-induced CXCL10 release but these inhibitory effects were not prevented by the PPAR-g antagonist GW9662. Ciglitazone did not affect early NF-κB activity and CXCL10 mRNA production.ConclusionsThus the thiazolidinediones inhibited asthmatic ASMC CXCL10 release under conditions when common asthma therapies were ineffective or enhanced it. They may provide an alternative strategy to reduce mast cell-ASM interactions and restore normal airway physiology in asthma.

Rosiglitazone elicits in vitro relaxation in airways and precision cut lung slices from a mouse model of chronic allergic airways disease

“…In vitro, human ASM cytokine secretion and proliferation have been shown to be suppressed by the PPAR␥ agonists RGZ and ciglitazone (CGZ) (10,27,30,34,37). However, only some of these anti-inflammatory and antiremodeling activities were inhibited by the selective PPAR␥ antagonist GW9662, suggesting both PPAR␥-dependent and -independent mechanisms (30, 34).…”

Anti-Inflammatory Dimethylfumarate: A Potential New Therapy for Asthma?

“…CXCL10 is secreted by ASMC after stimulation with proinflammatory cytokines such as TNF- α , IFN- γ , or IL-1 β , which activated MAPK JNK, NF- κ B, STAT 1, and the transcriptional coactivator CREB-binding protein [25, 39–41]. In addition, CXCL10 secretion by ASMC is sensitive to changes in cellular glutathione (GSH) levels [27], suggesting a link of this signaling pathway to the asthma-associated upregulation of mitochondria, which control the cellular redox system [42].…”

“…In addition, CXCL10 secretion by ASMC is sensitive to changes in cellular glutathione (GSH) levels [27], suggesting a link of this signaling pathway to the asthma-associated upregulation of mitochondria, which control the cellular redox system [42]. Interestingly, the thiazolidinedione ciglitazone strongly inhibited cytokine-induced CXCL10 protein without affecting CXCL10 mRNA level, suggesting that CXCL10 is regulated on the posttranslational level in ASMC [41]. In this context, it would be of interest if the posttranscriptional regulation of CXCL10 in asthma occurs through the recently described modified translation control [43].…”

“…Together these results emphasize a potential beneficial effect of Nrf2-mediated HO-1 induction in asthma. Regarding other anti-inflammatory actions of DMF, it reduced CXCL10 expression in cells stimulated with either a cytomix (IL-1 β , TNF- α , and IFN- γ in combination) or IFN- γ alone, which has been shown to be insensitive to GC therapy [25, 27, 41]. Thus DMF may act as an anti-inflammatory drug in steroid-resistant asthma and significantly reduce healthcare costs.…”

Novel approaches to the management of noneosinophilic asthma

“…In preclinical studies peroxisome proliferator-activated receptor-γ (PPARγ) agonists exert anti-inflammatory effects potentially relevant to the treatment of inflammatory airway diseases including asthma and COPD Belvisi and Hele, 2008;Seidel et al 2012;Stephen et al 2013;Bourke et al 2014;Lakshmi et al 2014;Lea et al 2014;Donovan et al 2015]. For example, PPARγ agonists reduce eosinophilic and neutrophilic lung infiltration in experimental animal models exposed to allergen or tobacco smoke [Bauer et al 2010;Lea et al 2014;Zhao et al 2014;Morissette et al 2015].…”