Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1869, Issue 1, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.bbamcr.2021.119135
Keywords
IL-11; IL-11 receptor; gp130; Proteolysis; ADAM10; RHBDL2
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [125440785 - SFB 877]
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IL-11, a member of the IL-6 family of cytokines, was originally discovered as a factor that promotes megakaryocyte maturation, but recent research has revealed its crucial roles in inflammation, fibrosis, and cancer. IL-11 initiates signaling through both classic and trans-signaling mechanisms, impacting the activation of cells that do not express the IL-11 receptor.
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.
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