Cargando…
Pro-inflammatory mechanisms of muscarinic receptor stimulation in airway smooth muscle
BACKGROUND: Acetylcholine, the primary parasympathetic neurotransmitter in the airways, plays an important role in bronchoconstriction and mucus production. Recently, it has been shown that acetylcholine, by acting on muscarinic receptors, is also involved in airway inflammation and remodelling. The...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2010
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955662/ https://www.ncbi.nlm.nih.gov/pubmed/20875145 http://dx.doi.org/10.1186/1465-9921-11-130 |
_version_ | 1782188062780948480 |
---|---|
author | Oenema, Tjitske A Kolahian, Saeed Nanninga, Janke E Rieks, Daniëlle Hiemstra, Pieter S Zuyderduyn, Suzanne Halayko, Andrew J Meurs, Herman Gosens, Reinoud |
author_facet | Oenema, Tjitske A Kolahian, Saeed Nanninga, Janke E Rieks, Daniëlle Hiemstra, Pieter S Zuyderduyn, Suzanne Halayko, Andrew J Meurs, Herman Gosens, Reinoud |
author_sort | Oenema, Tjitske A |
collection | PubMed |
description | BACKGROUND: Acetylcholine, the primary parasympathetic neurotransmitter in the airways, plays an important role in bronchoconstriction and mucus production. Recently, it has been shown that acetylcholine, by acting on muscarinic receptors, is also involved in airway inflammation and remodelling. The mechanism(s) by which muscarinic receptors regulate inflammatory responses are, however, still unknown. METHODS: The present study was aimed at characterizing the effect of muscarinic receptor stimulation on cytokine secretion by human airway smooth muscle cells (hASMc) and to dissect the intracellular signalling mechanisms involved. hASMc expressing functional muscarinic M(2 )and M(3 )receptors were stimulated with the muscarinic receptor agonist methacholine, alone, and in combination with cigarette smoke extract (CSE), TNF-α, PDGF-AB or IL-1β. RESULTS: Muscarinic receptor stimulation induced modest IL-8 secretion by itself, yet augmented IL-8 secretion in combination with CSE, TNF-α or PDGF-AB, but not with IL-1β. Pretreatment with GF109203X, a protein kinase C (PKC) inhibitor, completely normalized the effect of methacholine on CSE-induced IL-8 secretion, whereas PMA, a PKC activator, mimicked the effects of methacholine, inducing IL-8 secretion and augmenting the effects of CSE. Similar inhibition was observed using inhibitors of IκB-kinase-2 (SC514) and MEK1/2 (U0126), both downstream effectors of PKC. Accordingly, western blot analysis revealed that methacholine augmented the degradation of IκBα and the phosphorylation of ERK1/2 in combination with CSE, but not with IL-1β in hASMc. CONCLUSIONS: We conclude that muscarinic receptors facilitate CSE-induced IL-8 secretion by hASMc via PKC dependent activation of IκBα and ERK1/2. This mechanism could be of importance for COPD patients using anticholinergics. |
format | Text |
id | pubmed-2955662 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-29556622010-10-16 Pro-inflammatory mechanisms of muscarinic receptor stimulation in airway smooth muscle Oenema, Tjitske A Kolahian, Saeed Nanninga, Janke E Rieks, Daniëlle Hiemstra, Pieter S Zuyderduyn, Suzanne Halayko, Andrew J Meurs, Herman Gosens, Reinoud Respir Res Research BACKGROUND: Acetylcholine, the primary parasympathetic neurotransmitter in the airways, plays an important role in bronchoconstriction and mucus production. Recently, it has been shown that acetylcholine, by acting on muscarinic receptors, is also involved in airway inflammation and remodelling. The mechanism(s) by which muscarinic receptors regulate inflammatory responses are, however, still unknown. METHODS: The present study was aimed at characterizing the effect of muscarinic receptor stimulation on cytokine secretion by human airway smooth muscle cells (hASMc) and to dissect the intracellular signalling mechanisms involved. hASMc expressing functional muscarinic M(2 )and M(3 )receptors were stimulated with the muscarinic receptor agonist methacholine, alone, and in combination with cigarette smoke extract (CSE), TNF-α, PDGF-AB or IL-1β. RESULTS: Muscarinic receptor stimulation induced modest IL-8 secretion by itself, yet augmented IL-8 secretion in combination with CSE, TNF-α or PDGF-AB, but not with IL-1β. Pretreatment with GF109203X, a protein kinase C (PKC) inhibitor, completely normalized the effect of methacholine on CSE-induced IL-8 secretion, whereas PMA, a PKC activator, mimicked the effects of methacholine, inducing IL-8 secretion and augmenting the effects of CSE. Similar inhibition was observed using inhibitors of IκB-kinase-2 (SC514) and MEK1/2 (U0126), both downstream effectors of PKC. Accordingly, western blot analysis revealed that methacholine augmented the degradation of IκBα and the phosphorylation of ERK1/2 in combination with CSE, but not with IL-1β in hASMc. CONCLUSIONS: We conclude that muscarinic receptors facilitate CSE-induced IL-8 secretion by hASMc via PKC dependent activation of IκBα and ERK1/2. This mechanism could be of importance for COPD patients using anticholinergics. BioMed Central 2010 2010-09-28 /pmc/articles/PMC2955662/ /pubmed/20875145 http://dx.doi.org/10.1186/1465-9921-11-130 Text en Copyright ©2010 Oenema et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Oenema, Tjitske A Kolahian, Saeed Nanninga, Janke E Rieks, Daniëlle Hiemstra, Pieter S Zuyderduyn, Suzanne Halayko, Andrew J Meurs, Herman Gosens, Reinoud Pro-inflammatory mechanisms of muscarinic receptor stimulation in airway smooth muscle |
title | Pro-inflammatory mechanisms of muscarinic receptor stimulation in airway smooth muscle |
title_full | Pro-inflammatory mechanisms of muscarinic receptor stimulation in airway smooth muscle |
title_fullStr | Pro-inflammatory mechanisms of muscarinic receptor stimulation in airway smooth muscle |
title_full_unstemmed | Pro-inflammatory mechanisms of muscarinic receptor stimulation in airway smooth muscle |
title_short | Pro-inflammatory mechanisms of muscarinic receptor stimulation in airway smooth muscle |
title_sort | pro-inflammatory mechanisms of muscarinic receptor stimulation in airway smooth muscle |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955662/ https://www.ncbi.nlm.nih.gov/pubmed/20875145 http://dx.doi.org/10.1186/1465-9921-11-130 |
work_keys_str_mv | AT oenematjitskea proinflammatorymechanismsofmuscarinicreceptorstimulationinairwaysmoothmuscle AT kolahiansaeed proinflammatorymechanismsofmuscarinicreceptorstimulationinairwaysmoothmuscle AT nanningajankee proinflammatorymechanismsofmuscarinicreceptorstimulationinairwaysmoothmuscle AT rieksdanielle proinflammatorymechanismsofmuscarinicreceptorstimulationinairwaysmoothmuscle AT hiemstrapieters proinflammatorymechanismsofmuscarinicreceptorstimulationinairwaysmoothmuscle AT zuyderduynsuzanne proinflammatorymechanismsofmuscarinicreceptorstimulationinairwaysmoothmuscle AT halaykoandrewj proinflammatorymechanismsofmuscarinicreceptorstimulationinairwaysmoothmuscle AT meursherman proinflammatorymechanismsofmuscarinicreceptorstimulationinairwaysmoothmuscle AT gosensreinoud proinflammatorymechanismsofmuscarinicreceptorstimulationinairwaysmoothmuscle |