Interleukin-4, interleukin-13, signal transducer and activator of transcription factor 6, and allergic asthma

Abstract

Interleukin (IL)-4 and IL-13 share many biological activities. To some extent, this is because they both signal via a shared receptor, IL-4Ralpha. Ligation of IL-4Ralpha results in activation of Signal Transducer and Activator of Transcription factor 6 (STAT6) and Insulin Receptor Substrate (IRS) molecules. In T- and B-cells, IL-4Ralpha signaling contributes to cell-mediated and humoral aspects of allergic inflammation. It has recently become clear that IL-4 and IL-13 produced in inflamed tissues activate signaling in normally resident cells of the airway. The purpose of this review is to critically evaluate the contributions of IL-4- and IL-13-induced tissue responses, especially those mediated by STAT6, to some of the pathologic features of asthma including eosinophilic inflammation, airway hyperresponsiveness, subepithelial fibrosis and excessive mucus production. We also review the functions of some recently identified IL-4- and/or IL-13-induced mediators that provide some detail on molecular mechanisms and suggest an important contribution to host defense.

Fig. (1). Illustration 1. IL-4 and IL-13 signaling pathways

IL-4 is a ligand of the type lll-4 receptor composed of common γ and IL-4Rα subunits. Both IL-4 and IL-13 are ligands of the type II IL-4 receptor composed of IL-4Rα and IL-13Rα1 subunits. Receptor heterodimerization leads to activation of janus kinase (JAK) family members which phosphorylate tyrosine residues in the cytoplasmic tail of JL-4Rα. This leads to homodimerization of signal transducer and activator of transcription factor 6 (STAT6) monomers which then translocate to the nucleus and bind to the promoter regions of various genes. In concert, phosphorylated insulin receptor substrate (IRS) molecules provide binding sites for several src-homology domain 2 containing enzymes and adapter proteins. The downstream IRS-mediated signaling cascades include those mediated by phosphoinositol 3-kinase (PI3-K). The type I IL-4 receptor is shown in the activated, ligand-bound form and the type II IL-4 receptor is shown at rest.

Fig. (2). Illustration 2. A working model of the cellular mechanisms by which IL-4- and IL-13 induce pathology in the aitways

IL-4113 effects on dendritic cells contribute to inflammation. IL-4/13 effects on airway smooth muscle and epithelium contribute to airway hyperreactivity (AHR). IL-4/13-induced transforming growth factor beta (TGF-β) production by macrophages and eosinophils contributes to subepithelial fibrosis. IL-4/13 effects on airway epithelial cells contribute to excessive mucus production.