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mediated CXCL-8 release from human airway smooth muscle cells
1 Immunology, University of Manitoba, Winnipeg, Canada
2 Section of Thoracic Surgery, University of Manitoba, Winnipeg, Canada
3 physiology, Umanitoba, Winnipeg, Canada
* To whom correspondence should be addressed. E-mail: gounni{at}cc.umanitoba.ca.
Recent studies into the pathogenesis of airway disorders such as asthma have revealed a dynamic role for airway smooth muscle cells in the perpetuation of airway inflammation via secretion of cytokines and chemokines. In this study, we evaluated whether IL-17 could enhance IL-1
mediated CXCL-8 release from human airway smooth muscle cells (HASMC) and investigated the upstream and downstream signaling events regulating the induction of CXCL-8. CXCL-8 mRNA and protein induction were assessed by real-time RT-PCR and ELISA from primary HASMC cultures. HASMC transfected with site mutated AP-1/NF
B CXCL-8 promoter constructs were treated with selective p38, MEK-1/2 and PI3-K inhibitors to determine the importance of MAPK and PI3-K signaling pathways as well as AP-1 and NF-B promoter binding sites. We demonstrate IL-17 induced, and synergized with IL-1 to up-regulate CXCL-8 mRNA and protein levels. Erk-1/2 and p38 modulated IL-17 and IL-1 CXCL-8 promoter activity however IL-1 also activated the PI3-K pathway. The synergistic response mediating CXCL-8 promoter activity was dependent on both MAPK and PI3-K signal transduction pathways and required the cooperation of AP-1 and NF-B cis-acting elements upstream of the CXCL-8 gene. Collectively, our observations indicate MAPK and PI3-K pathways regulate the synergy of IL-17 and IL-1 to enhance CXCL-8 promoter activity, mRNA induction and protein synthesis in HASMC via the cooperative activation of AP-1 and NF-B trans-acting elements.
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