BackgroundMigration of airway smooth muscle cells (ASMCs) might contribute to increased airway smooth muscle mass in asthma. TH17 cells and TH17-associated cytokines are involved in the pathogenesis of asthma and might also contribute to airway remodeling.ObjectiveWe sought to explore the possibility that migration of ASMCs might contribute to airway remodeling through the action of TH17-related cytokines.MethodsThe effect of exogenous TH17 cytokines on ex vivo human ASMC migration was investigated by using a chemotaxis assay. The involvement of signaling pathways, including p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 MAPK, nuclear factor ΚB, and phosphoinos... More
BackgroundMigration of airway smooth muscle cells (ASMCs) might contribute to increased airway smooth muscle mass in asthma. TH17 cells and TH17-associated cytokines are involved in the pathogenesis of asthma and might also contribute to airway remodeling.ObjectiveWe sought to explore the possibility that migration of ASMCs might contribute to airway remodeling through the action of TH17-related cytokines.MethodsThe effect of exogenous TH17 cytokines on ex vivo human ASMC migration was investigated by using a chemotaxis assay. The involvement of signaling pathways, including p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 MAPK, nuclear factor ΚB, and phosphoinositide 3-kinase, was also examined.ResultsWe demonstrated that IL-17A, IL-17F, and IL-22 promote migration in a dose-dependent manner. We further demonstrated that ASMCs express receptors for IL-17RA, IL-17RC, and IL-22R1. Using mAbs directed against these receptors, we confirmed that TH17-associated cytokine–induced migration was dependent on selective receptor activation. Moreover, IL-17A and IL-17F exert their effects through signaling pathways that are distinct from those used by IL-22. The p38 MAPK inhibitor BIRB0796 inhibited the migration induced by IL-17A and IL-17F. PS1145, an inhibitor of nuclear factor ΚB, abolished the IL-22–induced migration.ConclusionThese data raise the possibility that TH17-associated cytokines promote human ASMC migration in vivo and suggest an important new mechanism for the promotion of airway remodeling in asthma.
