TH17 cytokines induce human airway smooth muscle cell migration

J Allergy Clin Immunol. 2011 Apr;127(4):1046-53.e1-2. doi: 10.1016/j.jaci.2010.12.1117. Epub 2011 Feb 22.

Abstract

Background: Migration of airway smooth muscle cells (ASMCs) might contribute to increased airway smooth muscle mass in asthma. T(H)17 cells and T(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(H)17-related cytokines.

Methods: The effect of exogenous T(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 κB, 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(H)17-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.

Conclusion: These data raise the possibility that T(H)17-associated cytokines promote human ASMC migration in vivo and suggest an important new mechanism for the promotion of airway remodeling in asthma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Airway Remodeling / physiology*
  • Asthma / immunology
  • Asthma / metabolism
  • Asthma / physiopathology
  • Cell Movement / physiology*
  • Cell Separation
  • Cytokines / immunology
  • Cytokines / metabolism*
  • Flow Cytometry
  • Humans
  • Myocytes, Smooth Muscle / cytology*
  • Myocytes, Smooth Muscle / metabolism
  • Signal Transduction / physiology
  • Th17 Cells / immunology
  • Th17 Cells / metabolism*

Substances

  • Cytokines