ID: 61: Apical and basolateral sorting of IL-11R facilitates co-sorting of gp130

Abstract

Interleukin (IL-)6 and IL-11 signal via homodimeric gp130 receptors, IL-6R α and IL-11R α , respectively. Preferential basolateral localization was demonstrated for the IL-6R and gp130. IL-11R is expressed in polarized cells cells as well. Moreover, IL-11 is involved in development of gastric tumors and regeneration of colon and heart tissue. Here, we show that the heterologous expression of IL-11R1 resulted in apical and basolateral membrane localization in Madin-Darby canine kidney (MDCK) cells. Transfer of the intracellular domain of the IL-6R to the IL-11R1 results in sorting of the chimeric protein to the basolateral membrane. After stimulation with IL-6 phosphorylation of signal transducer and activator of transcription-3 (STAT-3) was induced via basolaterally located IL-6R-gp130 complexes but not from the apical site. In the absence of IL-6R, gp130-induced STAT3-phosphorylation was also only induced after basolateral application of Hyper-IL-6, a fusion protein of IL-6 and the soluble IL-6R. STAT3 activation of IL-11 was, however, induced from apical and basolateral site. Exchange of the intracellular domains of IL-6R and IL-11R1, renders chimeric IL-11R only responsive from the basolatal site and chimeric IL-6R responsive from the apical and basolateral site. After expression of IL-11R1, MDCK cells became responsive to Hyper-IL-6 from the apical site, suggest that IL-11R1 expression resulted in re-sorting of gp130 also to the apical site. Finally, our data demonstrate that both receptors IL-6R and IL-11R1 are internalized with comparable kinetics by clathrin-mediated endocytosis. Our data showed, that IL-11R is expressed on apical and basolateral membranes which results in abrogation of basolateral sorting of gp130.