dsRNA-induced expression of thymic stromal lymphopoietin (TSLP) in asthmatic epithelial cells is inhibited by a small airway relaxant.
BACKGROUND
Thymic Stromal Lymphopoietin (TSLP) is considered a hub cytokine that activates dendritic cells and T-cells producing asthma-like Th₂-inflammation. Viral stimuli, a major cause of asthma exacerbations, have been shown to induce overexpression of TSLP in asthmatic epithelium. Capsazepine has multiple effects and is of interest because it relaxes human small airways. Here we have explored effects of capsazepine on viral surrogate (dsRNA)-induced TSLP and other cytokines (TNF-alpha, IL-8) in human bronchial epithelial cells (HBEC) from healthy and asthmatic donors.


METHODS
HBEC obtained from healthy and asthmatic subjects were grown and stimulated with dsRNA. Cells pre-treated with capsazepine (3-30 μM), dexamethasone (0.1-10 μM) or an IkappaB-kinase inhibitor (PS1145, 30 μM) were also exposed to dsRNA (10 μg/ml). Cells and supernatants were harvested for analyses of gene expression (RT-qPCR) and protein production (ELISA,Western blot).


RESULTS
dsRNA-induced TSLP, TNF-alpha, and IL-8 in asthmatic and non-asthmatic HBEC. Dexamethasone attenuated gene expression and protein release whereas capsazepine dose-dependently, and similar to a non-relaxant NFkB inhibitor (PS1145), completely inhibited dsRNA-induced TSLP and TNF-alpha in both healthy and asthmatic HBEC. Capsazepine reduced dsRNA-induced IL-8 and it prevented dsRNA-induced loss of the NF-κB repressor protein IkBα.


CONCLUSIONS
Additional to its human small airway relaxant effects we now demonstrate that capsazepine has potent anti-inflammatory effects on viral stimulus-induced cytokines in HBEC from healthy as well as asthmatic donors. Based on these data we suggest that exploration of structure-activity amongst the multifaceted capsazepinoids is warranted in search for compounds of therapeutic value in viral-induced, steroid-resistant asthma.
Unit of Respiratory Immunopharmacology, Department of Experimental Medical Science, BMC D12, Lund University, 22184 Lund, Sweden.
Angelica
A
Brandelius
Yulyana
Y
Yudina
Jenny
J
Calvén
Leif
L
Bjermer
Morgan
M
Andersson
Carl
C
Persson
Lena
L
Uller
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D001980:Bronchi / Q000187:drug effects* / Q000276:immunology; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology; D006801:Humans; D020672:I-kappa B Proteins / Q000032:analysis; D000072000:NF-KappaB Inhibitor alpha; D012330:RNA, Double-Stranded / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D000094632:Thymic Stromal Lymphopoietin
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D003907:Dexamethasone; C071423:capsazepine; D002211:Capsaicin; D000094632:Thymic Stromal Lymphopoietin