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Updated: Oct 17, 2025

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The role of proteolysis in interleukin-11 signaling

Juliane Lokau1, Birte Kespohl1, Sophia Kirschke1

  • 1Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany.

Biochimica Et Biophysica Acta. Molecular Cell Research
|October 8, 2021
PubMed

Although interleukin-11 (IL-11) was discovered more than 30 years ago, it remains an understudied member of the IL-6 family of cytokines. While it was originally discovered as a secreted factor that could foster megakaryocyte maturation and was therefore used as a recombinant protein to increase platelet production in patients with thrombocytopenia, recent research has established important roles for IL-11 in inflammation, fibrosis and cancer. In order to initiate signal transduction, IL-11 binds first to a non-signaling membrane-bound IL-11 receptor (IL-11R, classic signaling), which subsequently induces the formation of a heterodimer of the signal-transducing receptor gp130 that is shared with the other family members. Complex formation initiates several intracellular signaling cascades, most notably the Janus kinase/Signal Transducer and Activator of Transcription (Jak/STAT) pathway. We have recently identified a trans-signaling mechanism, in which IL-11 binds to soluble forms of the IL-11R (sIL-11R) and the agonistic IL-11/sIL-11R complex can activate cells that do not express the IL-11R and would usually not respond to IL-11. The generation of sIL-11R and thus the initiation of IL-11 trans-signaling is mediated by proteolytic cleavage. In this review, we summarize the current state of knowledge regarding IL-11R cleavage, highlight recent developments in IL-11 biology and discuss therapeutic opportunities and challenges in the light of IL-11 classic and trans-signaling.

Keywords:
ADAM10IL-11IL-11 receptorProteolysisRHBDL2gp130

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