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Phospho-proteomic analysis of interleukin (IL)-13 signaling in airway cells reveals SRC family kinase involvement in IL-13-induced inflammatory responses.

Archana Shankar,J. Mcalees,Michael A Wyder,Julie M Hargis,H. Ediga,Angela Cannata,Jana Latayan,Kenneth D. Greis,S. Madala,Ian P. Lewkowich

Published 2025 in International Archives of Allergy and Immunology

ABSTRACT

INTRODUCTION Allergic asthma is a chronic inflammatory airway disease driven by the cytokine interleukin-13 (IL-13). Although IL-13 signals through the canonical JAK1/TYK2/STAT6 pathway, our understanding of the totality of IL-13-induced signaling intermediates is incomplete. METHODS To address this, we performed an unbiased phospho-proteomic analysis of IL-13-stimulated A549 human airway epithelial cells. IL-13 stimulation led to differential phosphorylation at 145 unique serine/threonine residues across 92 proteins involved in diverse cellular processes. In silico analysis was used to predict novel signaling intermediates, and the role of these intermediates was tested in vitro using molecular techniques, and in vivo using an IL-13-induced model of asthma. RESULTS In silico analysis of differentially phosphorylated proteins revealed several pathways activated downstream of IL-13 exposure included RNA splicing, cytoskeletal remodeling, GTPase activity, and focal adhesion complex formation. Network analysis identified SRC, a non-receptor tyrosine kinase, as a potential regulator of IL-13-induced changes in phosphorylation. Kinetic molecular approaches confirmed that SRC is rapidly activated following IL-13 stimulation, prior to activation of the canonical IL-13 signaling intermediate STAT6 in both human and mouse lung fibroblasts. Pharmacological inhibition of SRC reduced IL-13-induced STAT6 phosphorylation and downstream gene expression in vitro. In vivo, SRC antagonism attenuated IL-13-induced airway hyperresponsiveness (AHR) without significantly affecting inflammatory cell infiltration or gene expression in bronchoalveolar lavage fluid. CONCLUSION These findings support a role for SRC in IL-13-driven airway responses and suggest they may represent therapeutic targets in allergic asthma.

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