Therapeutic Targeting of the Interleukin-4/Interleukin-13 Signaling Pathway: In Allergy and Beyond

Inflammation triggered by interleukin-4 (IL-4)/IL-13 is mediated by IL-4 and IL-13 receptors that are present on multiple cell types, including epithelial cells, smooth muscle, fibroblasts endothelial cells and immune cells. IL-4 exerts its activities by interacting with two specific cell surface receptors: one designated the type 1 IL-4 receptor (IL-4R); the other designated the type 2 IL-4R, a receptor complex that is also the functional receptor for IL-13. "Traditionally," IL-4 and IL-13 have been studied in the context of T helper 2-associated immune responses (i.e., type 2 immunity). In these settings, IL-4, IL-13 and their cognate receptor chains display pivotal roles where IL-4 is considered an instigator of type 2 immune responses and IL-13 an effector molecule. Thus, therapeutic targeting of the IL-4/IL-13 pathway is under extensive research, mainly for the treatment of allergic diseases. Nonetheless, in addition to IL-4's and IL-13's roles in type 2 immune responses, recent data highlight key activities for IL-4 and IL-13 in additional settings including metabolism, bone resorption, and even cognitive learning. This review summarizes the established knowledge that has accumulated regarding the roles of IL-4, IL-13, and their receptors in allergic diseases, with an emphasis on asthma, atopic dermatitis and eosinophilic esophagitis. Further, we provide an overview of the pharmacological entities targeting these cytokines and/or their receptors, which have been developed and clinically examined over the years. Finally, we will briefly highlight emerging evidence of potential new roles for IL-4 and IL-13 in other pathologies.