title: Capacity of capsazepinoids to relax human small airways and inhibit TLR3-induced TSLP and IFNβ production in diseased bronchial epithelial cells.
abstract: 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 IFNβ 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-IFNβ 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 LTD(4)-contracted small airways. TLR3-induced TSLP, TNFα, CXCL8, and IFNβ 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 IFNβ but none are more potent than capsazepine. Only capsazepine consistently inhibited TNFα and CXCL8 production and attenuated TLR3-induced epithelial NF-κB signalling. Hence, the present compounds did not separate between inhibition of TLR3-induced epithelial TSLP and IFNβ, 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 IFNβ and that these are distinct from mechanisms involved in relaxation of small airways by these compounds.
authors.affiliation: Division of Respiratory Immunopharmacology, Dept. Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Irma
authors.initials: I
authors.lastname: Mahmutovic-Persson
authors.forename: Martin
authors.initials: M
authors.lastname: Johansson
authors.forename: Angelica
authors.initials: A
authors.lastname: Brandelius
authors.forename: Jenny
authors.initials: J
authors.lastname: Calvén
authors.forename: Leif
authors.initials: L
authors.lastname: Bjermer
authors.forename: Yuliana
authors.initials: Y
authors.lastname: Yudina
authors.forename: Lena
authors.initials: L
authors.lastname: Uller
mesh_terms: D000328:Adult; D000368:Aged; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D001483:Base Sequence; D001980:Bronchi / Q000187:drug effects* / Q000276:immunology* / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000494:pharmacology; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D016899:Interferon-beta / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D055815:Young Adult; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D001993:Bronchodilator Agents; D016207:Cytokines; D012333:RNA, Messenger; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; C071423:capsazepine; D002211:Capsaicin; D000094632:Thymic Stromal Lymphopoietin