Proteolytic Cleavage Governs Interleukin-11 Trans-signaling

Cell Rep. 2016 Feb 23;14(7):1761-1773. doi: 10.1016/j.celrep.2016.01.053. Epub 2016 Feb 11.

Abstract

Interleukin (IL)-11 has been shown to be a crucial factor for intestinal tumorigenesis, lung carcinomas, and asthma. IL-11 is thought to exclusively mediate its biological functions through cell-type-specific expression of the membrane-bound IL-11 receptor (IL-11R). Here, we show that the metalloprotease ADAM10, but not ADAM17, can release the IL-11R ectodomain. Chimeric proteins of the IL-11R and the IL-6 receptor (IL-6R) revealed that a small juxtamembrane portion is responsible for this substrate specificity of ADAM17. Furthermore, we show that the serine proteases neutrophil elastase and proteinase 3 can also cleave the IL-11R. The resulting soluble IL-11R (sIL-11R) is biologically active and binds IL-11 to activate cells. This IL-11 trans-signaling pathway can be inhibited specifically by the anti-inflammatory therapeutic compound sgp130Fc. In conclusion, proteolysis of the IL-11R represents a molecular switch that controls the IL-11 trans-signaling pathway and widens the number of cells that can be activated by IL-11.

Keywords: ADAM10; ADAM17; interleukin-11; proteolysis; signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / genetics
  • ADAM Proteins / immunology*
  • ADAM10 Protein
  • ADAM17 Protein
  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / immunology*
  • Anti-Inflammatory Agents / pharmacology
  • Cell Line
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Inflammation
  • Interleukin-11 / genetics
  • Interleukin-11 / immunology*
  • Leukocyte Elastase / genetics
  • Leukocyte Elastase / immunology*
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Molecular Sequence Data
  • Monocytes / drug effects
  • Monocytes / immunology*
  • Monocytes / pathology
  • Myeloblastin / genetics
  • Myeloblastin / immunology*
  • Protein Binding
  • Proteolysis
  • Receptors, Interleukin-11 / genetics
  • Receptors, Interleukin-11 / immunology*
  • Receptors, Interleukin-6 / genetics
  • Receptors, Interleukin-6 / immunology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / pharmacology
  • Signal Transduction

Substances

  • Anti-Inflammatory Agents
  • IL11 protein, human
  • Interleukin-11
  • Membrane Proteins
  • Receptors, Interleukin-11
  • Receptors, Interleukin-6
  • Recombinant Fusion Proteins
  • Amyloid Precursor Protein Secretases
  • Leukocyte Elastase
  • Myeloblastin
  • ADAM Proteins
  • ADAM10 Protein
  • ADAM10 protein, human
  • ADAM17 Protein
  • olamkicept