Species Specificity of ADAM10 and ADAM17 Proteins in Interleukin-6 (IL-6) Trans-signaling and Novel Role of ADAM10 in Inducible IL-6 Receptor Shedding
Open accessAbstract
Hypomorphic ADAM17(ex/ex) mice showed defects in mucosal regeneration due to inefficient enhanced GFR shedding. ADAM17 is the main sheddase of interleukin-6 receptor (IL-6R) to induce IL-6 trans-signaling. However, serum levels of soluble murine IL-6R were not reduced in ADAM17(ex/ex) mice, and murine ADAM17 was not the major sheddase of murine IL-6R. Shedding of murine IL-6R by murine ADAM17 was rescued in chimeric murine IL-6R proteins containing any extracellular domain but not the transmembrane and intracellular domain of human IL-6R. Apoptosis is a physiological stimulus of ADAM17-mediated shedding of human IL-6R. Even though apoptosis induced IL-6R shedding in mice, the responsible protease was identified as ADAM10. ADAM10 also was identified as protease responsible for ionomycin-induced shedding of murine and human IL-6R. However, in ADAM10-deficient murine embryonic fibroblasts, compensatory shedding of human IL-6R was mediated by ADAM17, but loss of ADAM10-mediated shedding of murine IL-6R was compensated by an as-yet-unidentified protease. Finally, we identified physiological purinergic P2X7 receptor stimulation as a novel inducer of murine and human IL-6R shedding solely mediated by ADAM10. In conclusion, we describe an unexpected species specificity of ADAM10 and ADAM17 and identified ADAM10 as novel inducible sheddase of IL-6R in mice and humans, which might have consequences for the interpretation of phenotypes from ADAM17- and ADAM10-deficient mice.
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IL-6Rα is downregulated primarily by cleavage of the extracellular domain by ADAM10 and ADAM17 in humans, or only ADAM10 in mice.
“IL-6Rα appears to be downregulated primarily by cleavage of the extracellular domain by the metalloproteinases ADAM10 and ADAM17 in humans (74), or only ADAM 10 in mice (75)”
From T <sub>H</sub> 17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity (2020) · cites this paper as [75]
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“IL-6R appears to be down-regulated primarily by cleavage of the extracellular domain by the metalloproteinases ADAM10 and ADAM17 in humans (73) or only ADAM 10 in mice (74), which would appear to favor a shift from classic to IL-6 transsignaling in developing TH17 cells.”
BackgroundP2X7 on Mouse T Cells: One Channel, Many Functions
Rissiek, B., Haag, F., Boyer, O., Koch-Nolte, F., & Adriouch, S. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00204 · Cited by 116 · see citing works
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- Authors
- Garbers, C., Jänner, N., Chalaris, A., Moss, M. L., Floss, D. M., Meyer, D., Koch-Nolte, F., Rose-John, S., & Scheller, J.
- Affiliations
- Christian-Albrechts-Universität zu Kiel (DE)
- BioZyme (United States) (US)
- Heinrich Heine University Düsseldorf (DE)
- Corresponding author
- Scheller, Jürgen
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 286
- Issue
- 17
- Pages
- 14804-14811
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3083187
- OpenAlex
- W1968558772
- Cited by
- 201
- References
- 1
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 7 · 2023: 7 · 2022: 9 · 2021: 15 · 2020: 14 · 2019: 12 · 2018: 12 · 2017: 18 · 2016: 23 · 2015: 14 · 2014: 18 · 2013: 14 · 2012: 14
- FWCI
- 7.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (Project A2, SFB 877)
- Exzellenzclusters Entzündungsforschung
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- ADAM10, ADAM17, IL-6 receptor, IL-6 trans-signaling, receptor shedding, species specificity, apoptosis, P2X7 receptor, ionomycin, mucosal regeneration
- MeSH terms
- ADAM10 Protein, ADAM17 Protein, Animals, Humans, Membrane Proteins, Species Specificity, Signal Transduction, Interleukin-6, Receptors, Interleukin-6, Mice, ADAM Proteins, Amyloid Precursor Protein Secretases
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