Capacity of capsazepinoids to relax human small airways and inhibit TLR3-induced TSLP and IFN尾 production in diseased bronchial epithelial cells

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• 作者：Irma Mahmutovic-Persson^a ; Martin Johansson^b ; Angelica Brandelius^a ; Jenny Calvé ; n^a ; Leif Bjermer^c ; Yuliana Yudina^a ; Lena Uller^a ; ^{lena.uller@med.lu.se}
• 关键词：Asthma ; COPD ; TSLP ; Cytokines ; Inflammatory mediator ; Innate
• 刊名：International Immunopharmacology
• 出版年：2012
• 期刊代码：123_15675769
• 类别：med
• 出版时间：July, 2012
• 卷：13
• 期：3
• 页码：292-300
• 文件大小：1850 K

摘要

Thymic stromal lymphopoietin (TSLP), an immunomodulating potentially disease-inducing cytokine, is overproduced in TLR3-stimulated bronchial epithelial cells from asthmatic donors whereas production of antiviral IFN尾 is deficient. It is of therapeutic interest that capsazepine inhibits epithelial TSLP and relaxes human small airways with similar potencies. However, it is not known if other capsazepine-like compounds share such dual actions. This study explores epithelial anti-TSLP and anti-IFN尾 effects of capsazepine and novel capsazepine-like bronchorelaxants. We used primary bronchial epithelial cells from asthmatic and chronic obstructive pulmonary disease (COPD) donors, and human small airways dissected from surgically removed lungs. Seven novel capsazepinoids were about 10 times, and one compound (RES187) > 30 times, more potent than capsazepine as relaxants of LTD₄-contracted small airways. TLR3-induced TSLP, TNF伪, CXCL8, and IFN尾 mRNA and protein levels were dose-dependently and non-selectively inhibited by capsazepine, equally in cells from asthmatic and COPD donors. The novel compounds, except RES187, reduced TSLP and IFN尾 but none are more potent than capsazepine. Only capsazepine consistently inhibited TNF伪 and CXCL8 production and attenuated TLR3-induced epithelial NF-魏B signalling. Hence, the present compounds did not separate between inhibition of TLR3-induced epithelial TSLP and IFN尾, but all compounds, except capsazepine, did separate between the bronchorelaxant and the epithelial immune effects. We conclude that similar mechanisms may be involved in capsazepine-like inhibition of TLR3-induced epithelial TSLP and IFN尾 and that these are distinct from mechanisms involved in relaxation of small airways by these compounds.