Abstract
Increased airway smooth muscle (ASM) mass is a hallmark of airway remodeling in severe asthma. Th17-associated cytokines, particularly IL-17A, IL-17F, and IL-22, have been postulated to play a role in the pathogenesis of asthma. To investigate the in vitro effect of Th17 cytokines on the proliferation and survival of airway smooth muscle cells (ASMCs), human ASMCs from asthmatic and nonasthmatic subjects were incubated with IL-17A, IL-17F, or IL-22. The aforementioned cytokines demonstrated an ability to promote proliferation and survival of ASMCs from asthmatic and nonasthmatic subjects, which were mediated by selective activation of their corresponding receptors on ASMCs, including IL-17RA, IL-17RC, or IL-22R1, respectively. IL-17A and IL-17F-induced proliferation of ASMCs was dependent on ERK1/2 MAPK pathway, while IL-22-induced proliferation involved both ERK1/2 MAPK and NF-κB pathways. The involvement of signaling pathways was further confirmed by the inhibition of proliferation by knockdown of ERK1/2 MAPK or NF-κB p65 expression with pathway-specific siRNA. Together, our results show that Th17-associated cytokines promote proliferation and reduce the apoptotic rate of human ASMCs, raising the possibility that Th17 cytokines may contribute to increasing airway smooth muscle mass and airway remodeling in asthma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Asthma / metabolism
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Asthma / pathology
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Benzamides / pharmacology
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Bronchi / metabolism
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Bronchi / pathology
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Cell Proliferation / drug effects*
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Cell Survival / drug effects
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Cells, Cultured
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Cytokines / pharmacology*
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Humans
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Immunohistochemistry
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Interleukin-17 / pharmacology
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Interleukin-22
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Interleukins / pharmacology
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Myocytes, Smooth Muscle / drug effects*
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Myocytes, Smooth Muscle / metabolism
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Myocytes, Smooth Muscle / pathology
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Phosphorylation / drug effects
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RNA Interference
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Receptors, Interleukin / metabolism
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Receptors, Interleukin-17 / metabolism
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Sesquiterpenes / pharmacology
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Sesquiterpenes, Guaiane
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Signal Transduction / drug effects
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Th17 Cells / metabolism*
Substances
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2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
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Benzamides
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Cytokines
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Interleukin-17
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Interleukins
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NF-kappa B
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Receptors, Interleukin
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Receptors, Interleukin-17
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Sesquiterpenes
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Sesquiterpenes, Guaiane
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interleukin-22 receptor
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helenalin
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3