Cytokimera GIL-11 rescued IL-6R deficient mice from partial hepatectomy-induced death by signaling via non-natural gp130:LIFR:IL-11R complexes

Commun Biol. 2023 Apr 15;6(1):418. doi: 10.1038/s42003-023-04768-4.

Abstract

All except one cytokine of the Interleukin (IL-)6 family share glycoprotein (gp) 130 as the common β receptor chain. Whereas Interleukin (IL-)11 signal via the non-signaling IL-11 receptor (IL-11R) and gp130 homodimers, leukemia inhibitory factor (LIF) recruits gp130:LIF receptor (LIFR) heterodimers. Using IL-11 as a framework, we exchange the gp130-binding site III of IL-11 with the LIFR binding site III of LIF. The resulting synthetic cytokimera GIL-11 efficiently recruits the non-natural receptor signaling complex consisting of gp130, IL-11R and LIFR resulting in signal transduction and proliferation of factor-depending Ba/F3 cells. Besides LIF and IL-11, GIL-11 does not activate receptor complexes consisting of gp130:LIFR or gp130:IL-11R, respectively. Human GIL-11 shows cross-reactivity to mouse and rescued IL-6R-/- mice following partial hepatectomy, demonstrating gp130:IL-11R:LIFR signaling efficiently induced liver regeneration. With the development of the cytokimera GIL-11, we devise the functional assembly of the non-natural cytokine receptor complex of gp130:IL-11R:LIFR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Cytokine Receptor gp130 / genetics
  • Cytokine Receptor gp130 / metabolism
  • Hepatectomy*
  • Humans
  • Interleukin-11* / genetics
  • Interleukin-6 / metabolism
  • Leukemia Inhibitory Factor Receptor alpha Subunit
  • Mice
  • Receptors, Interleukin-11
  • Signal Transduction

Substances

  • Cytokine Receptor gp130
  • Interleukin-11
  • Receptors, Interleukin-11
  • Antigens, CD
  • Interleukin-6
  • LIFR protein, human
  • Leukemia Inhibitory Factor Receptor alpha Subunit