IL4R

IL4R, or interleukin-4 receptor, is a key component of the IL-4 signaling system in humans and other mammals. It primarily refers to the IL-4 receptor alpha chain (IL-4Rα), a member of the type I cytokine receptor family. The IL-4 receptor forms signaling complexes with different partners: the Type I receptor consists of IL-4Rα paired with the common gamma chain (γc, IL2RG) and is activated mainly by IL-4 in hematopoietic cells; the Type II receptor is composed of IL-4Rα and IL-13 receptor alpha 1 (IL-13Rα1) and can be activated by both IL-4 and IL-13 in a variety of cell types, including epithelial and smooth muscle cells. The IL4R gene encoding IL-4Rα is located on the human chromosome 16.

Upon binding of IL-4 or IL-13, the associated kinases become activated and phosphorylate tyrosine residues on the receptor, creating docking sites for downstream signaling molecules. The STAT family transcription factor STAT6 is the principal mediator of IL-4/IL-13 signaling, becoming phosphorylated, dimerizing, and translocating to the nucleus to regulate target gene expression. Other signaling pathways, including MAPK and PI3K pathways, may also be engaged depending on cell type and receptor context.

Biological roles of IL-4R signaling include promotion of B cell class switching to IgE, differentiation of T helper 2 (Th2) cells, and enhancement of mucus production and eosinophil recruitment—features associated with allergic and anti-parasitic responses. In non-hematopoietic tissues, Type II signaling can influence airway epithelium and smooth muscle, contributing to airway hyperreactivity in asthma.

Therapeutically, IL-4Rα is a target for interventions that dampen IL-4 and IL-13 signaling, such as monoclonal antibodies like dupilumab. Variants in IL4R have been linked to atopy and asthma risk in some populations, reflecting the gene’s role in immune regulation. There is also a soluble form of IL-4R (sIL-4R) arising from alternative splicing or shedding, which can modulate IL-4 activity.