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


CONCLUSIONS
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.
Meakins-Christie Laboratories and the Respiratory Division, Department of Medicine, McGill University, Montreal, Quebec, Canada.
Laila A
LA
Al-Alwan
Ying
Y
Chang
Carolyn J
CJ
Baglole
Paul-André
PA
Risse
Andrew J
AJ
Halayko
James G
JG
Martin
David H
DH
Eidelman
Qutayba
Q
Hamid
D019898:Autocrine Communication; D001980:Bronchi / Q000166:cytology*; D002465:Cell Movement / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000235:genetics / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D023063:Receptors, Interleukin-8B / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D020381:Interleukin-17; D023063:Receptors, Interleukin-8B; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases