Abstract
BackgroundPrevious work from our laboratory demonstrated that IL-4Rα expression on a myeloid cell type was responsible for enhancement of Th2-driven eosinophilic inflammation in a mouse model of allergic lung inflammation. Subsequently, we have shown that IL-4 signaling through type I IL-4 receptors on monocytes/macrophages strongly induced activation of the IRS-2 pathway and a subset of genes characteristic of alternatively activated macrophages. The direct effect(s) of IL-4 and IL-13 on mouse eosinophils are not clear. The goal of this study was determine the effect of IL-4 and IL-13 on mouse eosinophil function.MethodsStandard Transwell chemotaxis assay was used to assay migration of mouse eosinophils and signal transduction was assessed by Western blotting.ResultsHere we determined that (i) mouse eosinophils express both type I and type II IL-4 receptors, (ii) in contrast to human eosinophils, mouse eosinophils do not chemotax to IL-4 or IL-13 although (iii) pre-treatment with IL-4 but not IL-13 enhanced migration to eotaxin-1. This IL-4-mediated enhancement was dependent on type I IL-4 receptor expression: γC-deficient eosinophils did not show enhancement of migratory capacity when pre-treated with IL-4. In addition, mouse eosinophils responded to IL-4 with the robust tyrosine phosphorylation of STAT6 and IRS-2, while IL-13-induced responses were considerably weaker.ConclusionsThe presence of IL-4 in combination with eotaxin-1 in the allergic inflammatory milieu could potentiate infiltration of eosinophils into the lungs. Therapies that block IL-4 and chemokine receptors on eosinophils might be more effective clinically in reducing eosinophilic lung inflammation.
Highlights
Eosinophils play a critical role in the pathogenesis of allergic asthma, both in human asthmatics and in mouse models of the disease [1,2,3]
The insulin receptor substrate (IRS)-2 adaptor protein has the potential to trigger a variety of signaling pathways depending on the particular stimulus and cell type, including phosphoinositide 3-kinase (PI3K)/Akt, Grb/son-of-sevenless (Sos)/Rat sarcoma protein (Ras), mammalian target of rapamycin and protein kinase C (PKC) pathways
Given the importance of the eosinophil in allergic inflammation, we investigated whether mouse eosinophils responded directly to IL-4 and IL-13 in vitro and how these cytokines affected the chemotactic function of the cells
Summary
Eosinophils play a critical role in the pathogenesis of allergic asthma, both in human asthmatics and in mouse models of the disease [1,2,3]. Human eosinophils have been shown to express IL-4Ra, both on the cell surface [9] and in pre-formed stores on the outer membrane of their granules [10]. Engagement of both types of receptor initiates activation of the signal transducer and activator of transcription (STAT) pathway [11] but only type I IL-4 receptors are capable of strongly activating the insulin receptor substrate (IRS)-2 pathway in myeloid cells [12]. The goal of this study was determine the effect of IL-4 and IL-13 on mouse eosinophil function
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