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

Abstract

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.

Lung Tissue Damage Associated with Allergic Asthma in BALB/c Mice Could Be Controlled with a Single Injection of Mesenchymal Stem Cells from Human Bone Marrow up to 14 d After Transplantation

“…In our study, a significant increase in IL-13 was observed in the OVA-challenged animals compared to nonchallenged animals. Tissue damage was also caused by increased IL production, which is highly involved in the asthma inflammatory process 43 . IL-13 is related to airway hyperresponsiveness 44 , which was not measured in this study.…”

Eosinophilic Esophagitis: Review and Update

“…It is important to point out the importance of IL-4, IL-13, and their receptors in allergic diseases, with an emphasis on asthma, atopic dermatitis, and EoE ( 156 ). Therefore, the following agents are being investigated.…”

Novel topical and systemic therapies in atopic dermatitis

“…3.2 Lebrikizumab and tralokinumab: anti-IL-13 mAb IL-13, a major type 2 cytokine secreted from T lymphocytes, is highly elevated in AD both in blood and in skin [68]. Additionally, IL-13 is considered to be a key cytokine of type 2 inflammation with a number of effects on a variety of cells, excluding T lymphocytes [69]. Two antibodies against IL-13 have been studied in AD so far.…”