T sub(H17 cytokines induce human airway smooth muscle cell migration)

Background: Migration of airway smooth muscle cells (ASMCs) might contribute to increased airway smooth muscle mass in asthma. T sub(H17 cells and T) sub(H)17-associated cytokines are involved in the pathogenesis of asthma and might also contribute to airway remodeling. Objective: We sought to explore the possibility that migration of ASMCs might contribute to airway remodeling through the action of T sub(H17-related cytokines. Methods: The effect of exogenous T) sub(H)17 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 Kappa B, and phosphoinositide 3-kinase, was also examined. Results: We 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 T sub(H17-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 Kappa B, abolished the IL-22-induced migration. Conclusion: These data raise the possibility that T) sub(H)17-associated cytokines promote human ASMC migration in vivo and suggest an important new mechanism for the promotion of airway remodeling in asthma.