IL-17R activation of human airway smooth muscle cells induces CXCL-8 production via a transcriptional-dependent mechanism

Airway neutrophilia has been recognized as a predominant feature of acute lung disorders. While it has been shown that IL-17 induces expression of the CXC chemokines in the airways leading to neutrophil recruitment, the IL-17R expression in human ASM cells and the molecular mechanism by which IL-17 mediates neutrophilic chemo-attractant CXCL-8 (IL-8) production have not been determined. Our study showed that ASM cells express steady state IL-17R protein, mRNA and surface-bound receptor. Interestingly, airway sections from COPD patients revealed IL-17R-positive immunostaining within ASM bundles. IL-17 was capable of stimulating CXCL-8 protein release from ASM cells which was significantly decreased by neutralizing anti-IL-17 mAb. Furthermore, IL-17 induction of CXCL-8 mRNA and protein release from ASM cells was abrogated by transcriptional inhibitor actinomycin D. CXCL-8 promoter reporter analysis using wild type and site specific mutant constructs demonstrated a key role for AP1 and NF-κB  binding sites  in IL-17-induced CXCL-8 expression. These data demonstrate that IL-17 mediates CXCL-8 expression in ASM cells via a transcriptional mechanism depending on NF-κB and AP-1 pathways. Together, our findings suggest that ASM cells play an important role in airway neutrophilia.