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Int J Mol Sci. 2019 Jul 26;20(15). pii: E3677. doi: 10.3390/ijms20153677.

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

Author information

1
Institute of Biochemistry, University of Kiel, Otto-Hahn-Platz 9, 24118 Kiel, Germany.
2
Institute of Pathology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
3
Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Eppendorf, 20246, Hamburg, Germany.
4
Institute of Biochemistry, University of Kiel, Otto-Hahn-Platz 9, 24118 Kiel, Germany. cbeckerpauly@biochem.uni-kiel.de.

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

PMID:
31357561
DOI:
10.3390/ijms20153677
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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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