Soluble gp130 Prevents interleukin-6 and interleukin-11 Cluster Signaling but Not Intracellular Autocrine Responses

Sci Signal. 2018 Oct 2;11(550):eaar7388. doi: 10.1126/scisignal.aar7388.

Abstract

Interleukin-6 (IL-6) is a proinflammatory cytokine of the IL-6 family, members of which signal through a complex of a cytokine-specific receptor and the signal-transducing subunit gp130. The interaction of IL-6 with the membrane-bound IL-6 receptor (IL-6R) and gp130 stimulates "classic signaling," whereas the binding of IL-6 and a soluble version of the IL-6R to gp130 stimulates "trans-signaling." Alternatively, "cluster signaling" occurs when membrane-bound IL-6:IL-6R complexes on transmitter cells activate gp130 receptors on neighboring receiver cells. The soluble form of gp130 (sgp130) is a selective trans-signaling inhibitor, but it does not affect classic signaling. We demonstrated that the interaction of soluble gp130 with natural and synthetic membrane-bound IL-6:IL-6R complexes inhibited IL-6 cluster signaling. Similarly, IL-11 cluster signaling through the IL-11R to gp130 was also inhibited by soluble gp130. However, autocrine classic and trans-signaling was not inhibited by extracellular inhibitors such as sgp130 or gp130 antibodies. Together, our results suggest that autocrine IL-6 signaling may occur intracellularly.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autocrine Communication*
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Cytokine Receptor gp130 / metabolism*
  • HEK293 Cells
  • Humans
  • Interleukin-11 / metabolism*
  • Interleukin-6 / metabolism*
  • Mice
  • Protein Binding
  • Receptors, Interleukin-6 / metabolism
  • Signal Transduction*
  • Solubility

Substances

  • Interleukin-11
  • Interleukin-6
  • Receptors, Interleukin-6
  • Cytokine Receptor gp130