The interleukin-13 receptor α2 chain: an essential component for binding and internalization but not for interleukin-13–induced signal transduction through the STAT6 pathway

Abstract

The interleukin-13 receptor (IL-13R) complex is composed of 2 different chains, IL-13Rα1 (also known as IL-13Rα′) and IL-13Rα2 (also known as IL-13Rα). For a functional IL-13 receptor, the IL-13Rα1 chain forms a productive complex with the primary IL-4 binding protein (IL-4Rα also known as IL-4Rβ). However, the function of the IL-13Rα2 chain is not clear even though this chain binds IL-13 with high affinity. This study demonstrates that IL-13Rα2 can undergo internalization after binding to ligand without causing activation of its signaling pathways. These conclusions were drawn on the basis of (1) internalization of 125I–IL-13 in Chinese hamster ovarian (CHO-K1) and T98G glioblastoma cells transiently transfected with the IL-13Rα2 chain; (2) a recombinant chimeric fusion protein comprising IL-13 and a mutated form ofPseudomonas exotoxin (termed IL13-PE38QQR or IL-13 toxin) is specifically cytotoxic to IL-13Rα2–transfected CHO-K1 cells in a gene dose-dependent manner, whereas cells transfected with vector alone were not sensitive; and (3) IL-13 did not cause activation of signal transduction and activation of transcription 6 (STAT6) in IL-13Rα2–transfected cells. IL-13 efficiently caused activation of STAT6 protein in cells transfected with the IL-13Rα1 and IL-4Rα chains, and IL-13Rα2 inhibited this activation. Taken together, these observations indicate that internalization of IL-13Rα2 is signal independent and that this property of IL-13Rα2 can be exploited for receptor-directed cancer therapy.