Autocrine-regulated airway smooth muscle cell migration is dependent on IL-17-induced growth-related oncogenes

Abstract

Background: Airway smooth muscle cell (ASMC) migration is one of the proposed mechanisms underlying the increased airway smooth muscle mass seen in airway remodeling of patients with severe asthma. IL-17-related cytokines are a new subgroup of inflammatory mediators that have been suggested to play a role in regulating smooth muscle function. We hypothesized that IL-17-induced chemokine production from smooth muscle cells can contribute to migration of additional smooth muscle cells in the airways of asthmatic patients.

Objective: We sought to investigate the effect of IL-17 on smooth muscle-derived chemokines and to examine the mechanisms involved in their production and contribution to the increase in airway smooth muscle migration.

Methods: The effect of IL-17-induced supernatants on human ASMC migration was investigated. IL-17-induced growth-related oncogene (GRO) production and mRNA expression was assessed by using ELISA and RT-PCR, respectively. The direct effect of GROs on ASMC migration and the involvement of the CXCR2 receptor were also examined.

Results: IL-17-induced supernatants promoted ASMC migration. After IL-17 stimulation, GROs were the most abundant chemokines produced from ASMCs, and blocking their effect by using neutralizing antibodies significantly inhibited ASMC migration. In addition, a combination of recombinant human GRO-α, GRO-β, and GRO-γ was able to promote significant migration of ASMCs that was mediated through the CXCR2 receptor.

Conclusion: These findings suggest that IL-17-induced GROs can be an important mediator of ASMC migration and therefore might contribute to the pathogenesis of airway remodeling in asthmatic patients.