IL-13R(alpha)2, a decoy receptor for IL-13 acts as an inhibitor of IL-4-dependent signal transduction in glioblastoma cells.
Interleukin (IL)-4 and IL-13 share the type II IL-4 receptor for cell signaling. We show that despite expressing the necessary signaling components, glioblastoma cells failed to respond to either IL-4 or IL-13. This was in part because of the expression of a high-affinity IL-13-binding transmembrane protein IL-13R(alpha)2 that inhibited IL-13-mediated Stat6 activation by acting as a decoy receptor. In contrast, normal human astrocytes that did not express the IL-13R(alpha)2 gene efficiently induced Stat6 activation in response to both IL-4 and IL-13. Transient expression of the IL-13R(alpha)2 transgene in nonexpressing heterologous cells inhibited not only IL-13- but also IL-4-mediated signal transduction and Stat6-responsive gene expression. The inhibition was likely mediated through the physical interaction between the short intracellular domain of the IL-13R(alpha)2 protein and the cytoplasmic domain of the IL-4R(alpha) chain that harbors the Stat6 docking sites. Thus, IL-13R(alpha)2 acts as an inhibitor of IL-4-dependent signal transduction pathways via a novel mechanism that is independent of ligand binding.
Rahaman
Shaik Ohidar
SO
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Sharma
Pankaj
P
Harbor
Phyllis C
PC
Aman
M Javad
MJ
Vogelbaum
Michael A
MA
Haque
S Jaharul
SJ
D016475:3T3 Cells; D000818:Animals; D015870:Gene Expression / Q000502:physiology; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018793:Interleukin-13 / Q000502:physiology; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000502:physiology; D051379:Mice; D017434:Protein Structure, Tertiary; D018123:Receptors, Interleukin / Q000378:metabolism / Q000502:physiology*; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4 / Q000378:metabolism / Q000502:physiology; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics
C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4