Abstract
BackgroundPrevious findings support the concept that IL-9 may play a significant role in mediating both pro-inflammatory and changes in airway responsiveness that characterizes the atopic asthmatic state. We previously demonstrated that human airway smooth muscle (ASM) cells express a functional IL-9R that mediate CCL11 expression. However, the signaling pathway governing this effect is not well understood.Methodology/Principal Findings In this study, we showed that IL-9 mediated CCL11 expression in ASM cells does not rely on STAT6 or STAT5 but on STAT3 pathway. IL-9 induced rapid STAT3 activation in primary ASM cells that was not observed in case of STAT6 or STAT5. STAT3 binding to CCL11 promoter was also observed in vivo upon IL-9 stimulation of ASM cells. Disruption of STAT3 activity with SH2 domain binding inhibitory peptide results in significant reduction of IL-9 mediated CCL11 promoter activity. DN STAT3β over-expression in ASM cells, but not Ser 727 STAT3 or STAT6 DN, abolishes IL-9 mediated CCL11 promoter activity. Finally, STAT3 but not STAT6 silenced ASM cells showed significant reduction in IL-9 mediated CCL11 promoter activity and mRNA expression.Conclusion/SignificanceTaken together, our results indicate that IL-9 mediated CCL11 via STAT3 signalling pathway may play a crucial role in airway inflammatory responses.
Highlights
Airway smooth muscle (ASM) cells are key structural cells involved in the pathogenesis of many airway diseases by contributing to inflammation and airway hyperresponsiveness[1]
We have previously demonstrated that IL-9 induces CCL11 expression in airway smooth muscle (ASM) cells[14]
Our previous work showed that primary ASM cells express a functional IL-9R in vitro; and in vivo ASM bundle from atopic asthmatics displayed higher expression of IL-9R compared to normal controls[14]
Summary
Airway smooth muscle (ASM) cells are key structural cells involved in the pathogenesis of many airway diseases by contributing to inflammation and airway hyperresponsiveness[1]. The IL-9 and IL-9R gene are located on chromosomal region where a linkage with asthma and its risk factors has been demonstrated[6,7].the development of transgenic mice over-expressing IL-9 has suggested a potential role for this cytokine in the development of airway eosinophilia, mast cell hyperplasia, mucus production and airway hyperresponsiveness[8,9,10]. These findings support the concept that IL-9 may significantly be involved in mediating both pro-inflammatory and changes in airway responsiveness that characterizes the atopic asthmatic state. The signaling pathway governing this effect is not well understood
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