Regulation of IL-4 mediated signalling in primary human bronchial fibroblasts by IL-13Rα2

• Main Author: Campbell Harding, Gemma
• Other Authors: Davies, Donna ; Andrews, Allison-Lynn
• Published: University of Southampton 2011
• Subjects: 610; RC Internal medicine
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.635448

Fibroblasts are key effector cells involved in airway inammation and remodelling in asthma. Interleukin (IL)-4 and IL-13 are important cytokines in the asthma phenotype which act on fibroblasts and other cell types. These cytokines exhibit overlapping functions through use of a common receptor, IL-4Rα:IL-13Rα1. Another receptor, IL 13 Receptor α2 (IL-13Rα2), originally thought to be a decoy receptor for IL-13, has recently been shown to attenuate responses to IL-4 as well as IL-13, by an unknown mechanism. In this thesis, I tested the hypothesis that IL-13Rα2 is responsible for the regulation of IL-4 mediated signalling in bronchial fibroblasts and that regulation by IL-13Rα2 is altered in asthma. The expression of IL-4 and IL-13 receptors on human bronchial fibroblasts (HBFs) was highly dynamic. IL-13Rα2 expression was significantly increased in response to both IL-4 and IL-13 over 24 hours, requiring de novo protein synthesis. A significant rapid reduction in IL-4Rα expression was also observed in response to either ligand, although levels rapidly returned to normal after removal of the stimulus. Use of a neutralizing antibody showed that induction of IL 13Rα2 suppressed STAT-6 activation and the pro-inflammatory effects of IL-4 and IL-13. No difference was observed in receptor expression levels or the regulatory effects of IL-13Rα2 between healthy and asthmatic subjects. IL-13Rα2 was also up regulated by a range of Th1 stimuli including IFN and IFNβ, as well as double stranded RNA (dsRNA), with no disease-related differences. The up-regulation of IL 13Rα2 in response to dsRNA hampered attempts to knock down surface expression of IL-13Rα2 using siRNA, but revealed a potential role for IL-13Rα2 in the anti-viral response due to its ability to down-regulate responses to IL-4 and IL-13. An over expression model of IL-13Rα2 identified the potential for IL-4 to cause activation of STAT3 mediated by IL-13Rα2. In HBFs naturally expressing high levels of IL-13Rα2, addition of IL-4, but not IL-13, signifycantly increased activation of STAT3, a transcription factor associated with cell survival. Whilst IL-13Rα2 may have beneficial anti-inflammatory effects by suppressing STAT-6 mediated responses, further work is required to determine potential pro-fibrotic consequences of IL-4/IL-13Rα2 mediated STAT3 activation in HBFs. Since no difference was observed in IL-13Rα2 expression or in its anti-inflammatory efficacy in HBFs from normal or asthmatic donors, these data suggest that the atopic environment is more important than intrinsic differences in the ability of asthma-derived fibroblasts to respond to IL-4 and IL-13.