Differences in Shedding of the Interleukin-11 Receptor by the Proteases ADAM9, ADAM10, ADAM17, Meprin α, Meprin β and MT1-MMP

Int J Mol Sci. 2019 Jul 26;20(15):3677. doi: 10.3390/ijms20153677.

Abstract

Interleukin-11 (IL-11) has been associated with inflammatory conditions, bone homeostasis, hematopoiesis, and fertility. So far, these functions have been linked to classical IL-11 signaling via the membrane bound receptor (IL-11R). However, a signaling cascade via the soluble IL-11R (sIL-11R), generated by proteolytic cleavage, can also be induced. This process is called IL-11 trans-signaling. A disintegrin and metalloprotease 10 (ADAM10) and neutrophil elastase were described as ectodomain sheddases of the IL-11R, thereby inducing trans-signaling. Furthermore, previous studies employing approaches for the stimulation and inhibition of endogenous ADAM-proteases indicated that ADAM10, but not ADAM17, can cleave the IL-11R. Herein, we show that several metalloproteases, namely ADAM9, ADAM10, ADAM17, meprin β, and membrane-type 1 matrix metalloprotease/matrix metalloprotease-14 (MT1-MMP/MMP-14) when overexpressed are able to shed the IL-11R. All sIL-11R ectodomains were biologically active and capable of inducing signal transducer and activator of transcription 3 (STAT3) phosphorylation in target cells. The difference observed for ADAM10/17 specificity compared to previous studies can be explained by the different approaches used, such as stimulation of protease activity or making use of cells with genetically deleted enzymes.

Keywords: ADAM; IL-11; IL-6; MMP; interleukin; meprin; metalloproteases; trans-signaling.

MeSH terms

  • ADAM Proteins / chemistry
  • ADAM Proteins / metabolism*
  • Humans
  • Matrix Metalloproteinase 14 / chemistry
  • Matrix Metalloproteinase 14 / metabolism*
  • Phosphorylation
  • Proteolysis
  • Receptors, Interleukin-11 / chemistry
  • Receptors, Interleukin-11 / metabolism*
  • Receptors, Interleukin-6 / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Structure-Activity Relationship
  • Tiopronin / metabolism*

Substances

  • Receptors, Interleukin-11
  • Receptors, Interleukin-6
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Tiopronin
  • ADAM Proteins
  • MMP14 protein, human
  • Matrix Metalloproteinase 14