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

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Capacity of capsazepinoids to relax human small airways and inhibit TLR3-induced TSLP and IFNβ production in diseased bronchial epithelial cells. / Mahmutovic Persson, Irma; Johansson, Martin; Brandelius, Angelica; Calvén, Jenny; Bjermer, Leif; Yudina, Yuliana; Uller, Lena.

I: International Immunopharmacology, Vol. 13, Nr. 3, 2012, s. 292-300.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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T1 - Capacity of capsazepinoids to relax human small airways and inhibit TLR3-induced TSLP and IFNβ production in diseased bronchial epithelial cells.

AU - Mahmutovic Persson, Irma

AU - Johansson, Martin

AU - Brandelius, Angelica

AU - Calvén, Jenny

AU - Bjermer, Leif

AU - Yudina, Yuliana

AU - Uller, Lena

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

KW - Innate

KW - Inflammatory mediator

KW - Cytokines

KW - TSLP

KW - Asthma

KW - COPD

U2 - 10.1016/j.intimp.2012.04.007

DO - 10.1016/j.intimp.2012.04.007

M3 - Article

VL - 13

SP - 292

EP - 300

JO - International Immunopharmacology

T2 - International Immunopharmacology

JF - International Immunopharmacology

SN - 1878-1705

IS - 3

ER -