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Synthetic strategies to activate cytokine receptors so far only address standard dimeric cytokine receptor assemblies. The 19 ligands of the tumor necrosis factor superfamily (TNFSF), however, form noncovalent trimers and receptor trimerization is considered to be essential for receptor activation. Synthetic TNFR1, TNFR2, and Fas/CD95 receptors were activated by synthetic trimeric ligands which induced NF-κB signaling or Caspase-induced apoptosis. Albeit dimeric receptor activation did not induce synthetic TNFR1 and TNFR2 signaling, dimeric FasL induced extenuated apoptosis. Simultaneous integration of dimeric Interleukin (IL-)6 receptor gp130 and trimeric Fas as synthetic cytokine receptors in one cell enabled binary cell fate decisions, gp130-mediated proliferation or Fas-mediated apoptosis. In summary, our modular fully synthetic cytokine signaling system allows precisely orchestrated cellular responses to selectively induce pro- and anti-apoptotic signaling via canonical dimeric receptors of the IL-6 family and non-canonical trimeric receptor complexes of the TNF superfamily., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Interleukin (IL)-11 signaling is involved in various processes, including epithelial intestinal cell regeneration and embryo implantation. IL-11 signaling is initiated upon binding of IL-11 to IL-11R1 or IL-11R2, two IL-11α-receptor splice variants, and gp130. Here, we show that IL-11 signaling via IL-11R1/2:gp130 complexes occurs on both the apical and basolateral sides of polarized cells, whereas IL-6 signaling via IL-6R:gp130 complexes is restricted to the basolateral side. We show that basolaterally supplied IL-11 is transported and released to the apical extracellular space via transcytosis in an IL-11R1-dependent manner. By contrast, IL-6R and IL-11R2 do not promote transcytosis. In addition, we show that transcytosis of IL-11 is dependent on the intracellular domain of IL-11R1 and that synthetic transfer of the intracellular domain of IL-11R1 to IL-6R promotes transcytosis of IL-6. Our data define IL-11R as a cytokine receptor with transcytotic activity by which IL-11 and IL-6:soluble IL-6R complexes are transported across cellular barriers., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)