The interleukin-6 receptor Asp358Ala single nucleotide polymorphism rs2228145 confers increased proteolytic conversion rates by ADAM proteases
Open accessAbstract
The pleiotropic activities of Interleukin (IL-)6 are controlled by membrane-bound and soluble forms of the IL-6 receptor (IL-6R) in processes called classic and trans-signaling, respectively. The coding single nucleotide polymorphism (SNP) rs2228145 of the Interleukin 6 receptor (IL-6R Asp358Ala variant) is associated with a 2-fold increase in soluble IL-6R (sIL-6R) serum levels resulting in reduced IL-6-induced C-reactive protein (CRP) production and a reduced risk for coronary heart disease. It was suggested that the increased sIL-6R level leads to decreased IL-6 classic or increased IL-6 trans-signaling. Irrespective of the functional outcome of increased sIL-6R serum level, it is still under debate, whether the increased sIL-6R serum levels emerged from differential splicing or ectodomain shedding. Here we show that increased proteolytic ectodomain shedding mediated by the A Disintegrin and metalloproteinase domain (ADAM) proteases ADAM10 and ADAM17 caused increased sIL-6R serum level in vitro as well as in healthy volunteers homozygous for the IL-6R Asp358Ala allele. Differential splicing of the IL-6R appears to have only a minor effect on sIL-6R level. Increased ectodomain shedding resulted in reduced cell-surface expression of the IL-6R Asp358Ala variant compared to the common IL-6R variant. In conclusion, increased IL-6R ectodomain shedding is a mechanistic explanation for the increased serum IL-6R levels found in persons homozygous for the rs2228145 IL-6R Asp358Ala variant.
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The IL6RA variant rs2228145 leads to increased proteolytic cleavage of IL-6Rα, reducing membrane-bound IL-6Rα and increasing serum levels.
“The IL6RA variant rs2228145, which leads to increased proteolytic cleavage of IL-6Rα and thus a reduction in membrane-bound IL-6Rα in favor of increased serum levels (79)”
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 [79]
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- Authors
- Garbers, C., Monhasery, N., Aparicio-Siegmund, S., Lokau, J., Baran, P., Nowell, M. A., Jones, S. A., Rose-John, S., & Scheller, J.
- Affiliations
- Christian-Albrechts-Universität zu Kiel (DE)
- Heinrich Heine University Düsseldorf (DE)
- Cardiff University (GB)
- Corresponding author
- Scheller, Jürgen
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 1842
- Issue
- 9
- Pages
- 1485-1494
- ISSN
- 0925-4439 (ISSN-L)
- OpenAlex
- W2052096345
- Cited by
- 155
- References
- 6
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 15 · 2023: 9 · 2022: 13 · 2021: 13 · 2020: 20 · 2019: 14 · 2018: 10 · 2017: 14 · 2016: 13 · 2015: 8 · 2014: 2
- FWCI
- 5.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 365 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (DFG SCHE 907/2-1, SFB877)
- 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 › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- IL-6 receptor, rs2228145, soluble IL-6 receptor, ADAM10, ADAM17, ectodomain shedding, trans-signaling, differential splicing, C-reactive protein, coronary artery disease, single nucleotide polymorphisms
- MeSH terms
- ADAM10 Protein, ADAM17 Protein, Animals, Cells, Cultured, Embryo, Mammalian, Fibroblasts, Fluorescent Antibody Technique, Humans, Membrane Proteins, RNA, Messenger, Blotting, Western, Signal Transduction, Interleukin-6, Apoptosis, Mice, Knockout, Receptors, Interleukin-6, Reverse Transcriptase Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Cell Proliferation, Mice, ADAM Proteins, Amyloid Precursor Protein Secretases, Precursor Cells, B-Lymphoid, Proteolysis, Real-Time Polymerase Chain Reaction
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