Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man
Open accessAbstract
Liver-derived acute phase proteins (APPs) emerged as powerful predictors of cardiovascular disease and cardiovascular events, but their functional role in atherosclerosis remains enigmatic. We report that the gp130 receptor, which is a key component of the inflammatory signaling pathway within hepatocytes, influences the risk of atherosclerosis in a hepatocyte-specific gp130 knockout. Mice on an atherosclerosis-prone genetic background exhibit less aortic atherosclerosis (P < 0.05) with decreased plaque macrophages (P < 0.01). Translating these findings into humans, we show that genetic variation within the human gp130 homologue, interleukin 6 signal transducer (IL6ST), is significantly associated with coronary artery disease (CAD; P < 0.05). We further show a significant association of atherosclerotic disease at the ostium of the coronary arteries (P < 0.005) as a clinically important and heritable subphenotype in a large sample of families with myocardial infarction (MI) and a second independent population–based cohort. Our results reveal a central role of a hepatocyte-specific, gp130-dependent acute phase reaction for plaque development in a murine model of atherosclerosis, and further implicate IL6ST as a genetic susceptibility factor for CAD and MI in humans. Thus, the acute phase reaction should be considered an important target for future drug development in the management of CAD.
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GWAS, meta-analysis, exome analysis and SNP mapping have associated IL-6, IL-6R and gp130 with inflammatory diseases such as RA and coronary artery disease.
“Genome-wide association studies (GWAS), meta-analysis, exome analysis and single nucleotide polymorphism (SNP) mapping have associated IL-6, IL-6R and gp130 with inflammatory diseases such as RA and coronary artery disease (263–269).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [267]
The Results section (“Human genetic association of polymorphisms in the IL6ST/gp130 gene”; page unavailable) reports an association between an IL6ST/gp130 SNP and coronary artery disease, supporting the SNP-mapping portion of the claim. The passages do not establish associations for IL-6 or IL-6R, rheumatoid arthritis, or findings from GWAS, meta-analysis, or exome analysis. (LLM, conf=0.88)
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Drechsler, M., & Soehnlein, O. (2013) · Journal of Innate Immunity · doi:10.1159/000348795 · Cited by 15 · see citing works
Chen, Y., van Zon, S., Adams, A. T., Schmidt‐Arras, D., Laurence, A. D. J., & Uhlig, H. H. (2023) · Journal of Clinical Immunology · doi:10.1007/s10875-023-01603-7 · Cited by 13 · see citing works
“…p l e s c l e r o s i s ( E u r op ea n ) [ 37 ] ; p r o s t a t e ca n ce r ( A fr i ca n A m e r i ca n ) [ 38 ] ; a t h e r o s c l e r o s i s [ 39 ] ; I 454 T i s a ss o c i a t e d w it h s u s ce p ti b ilit y t o c o r n ea l i n fi lt r a ti v e e v e n t s o f s o f t c on t ac t l e n s…”
BackgroundLiver damage promotes pro‐inflammatory T‐cell responses against apolipoprotein B‐100
Plochg, B. F. J., Englert, H., Rangaswamy, C., Konrath, S., Malle, M., Lampalzer, S., Beisel, C., Wollin, S., Frye, M., Aberle, J., et al. (2021) · Journal of Internal Medicine · doi:10.1111/joim.13434 · Cited by 14 · see citing works
Molecular Mechanisms Underlying Atherosclerosis and Current Advances in Targeted Therapeutics
Zhu, B. J. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27020634 · Cited by 10 · see citing works
“Furthermore, genetic variations in the human IL6ST gene (which encodes gp130) are associated with increased risk of CAD [154].”
Zhou, M., Dai, W., Cui, Y., Liu, H., & Li, Y. (2020) · Annals of Translational Medicine · doi:10.21037/atm.2020.02.27 · Cited by 12 · see citing works
“A zoological study has shown that hepaticspecific gp130-/- mice are resistant to atherosclerosis, probably owing to macrophage infiltration of atherosclerotic plaques and reduction of acute phase protein levels (5).”
BackgroundHo, Y. S., Lai, M., Liu, S.-J., Lin, C. T., Naruishi, K., Takashiba, S., & Chou, H.-H. (2009) · Journal of Periodontal Research · doi:10.1111/j.1600-0765.2008.01150.x · Cited by 12 · see citing works
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A Single-Cell Survey of Cellular Heterogeneity in Human Great Saphenous Veins
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“Our results illustrated that IL6ST, a signaling transducer for various inflammatory cytokines and risk gene for CAD, was a direct target downstream of KLF9 [42] (Figure 4G).”
Scheller, J., Berg, A. F., Moll, J. M., Floss, D. M., & Jungesblut, C. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155550 · Cited by 11 · see citing works
Vascular effects of glycoprotein130 ligands--part II: biomarkers and therapeutic targets.
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“Experimentally induced APRsignaling, restricted specifically to hepatocytes, has been shown to accelerate atherosclerosis in Apoe mice (52).”
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Hepatocyte gp130 Deficiency Reduces Vascular Remodeling After Carotid Artery Ligation
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Gene expression profiling of coronary artery disease and its relation with different severities
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Regulation of alpha cell function by gp130 receptor signalling in a rodent model of type 2 diabetes
Chow, S. (2014) · cIRcle (University of British Columbia) · doi:10.14288/1.0167077
- Authors
- Luchtefeld, M., Schunkert, H., Stoll, M., Selle, T., Lorier, R., Grote, K., Sagebiel, C., Jagavelu, K., Tietge, U. J. F., Assmus, U., Streetz, K., Hengstenberg, C., Fischer, M., Mayer, B., Maresso, K., El Mokhtari, N. E., Schreiber, S., Müller, W., Bavendiek, U., Grothusen, C., Drexler, H., Trautwein, C., Broeckel, U., & Schieffer, B.
- Affiliations
- Medizinische Hochschule Hannover (DE)
- University Hospital Schleswig-Holstein (DE)
- University of Münster (DE)
- Medical College of Wisconsin (US)
- University Medical Center Groningen (NL)
- RWTH Aachen University (DE)
- University Hospital Regensburg (DE)
- 2Medizinische Klinik II, Universitätsklinikum Schleswig-Holstein, 23562 Lübeck, Germany
- 8Department of Cardiology, Institute for Clinical Molecular Biology and Department of General Medicine, Christian Albrecht University, D-2300 Kiel, Germany
- Christian-Albrechts-Universität zu Kiel (DE)
- 9Department of Experimental Immunology, Gesellschaft für Biotechnologische Forschung, D-38124 Braunschweig, Germany
- ORCID
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2007-07-30
- Volume
- 204
- Issue
- 8
- Pages
- 1935-1944
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2118681
- OpenAlex
- W2168966851
- Cited by
- 69
- References
- 35
- Citations by year
- 2026: 2 · 2025: 1 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 6 · 2016: 1 · 2015: 3 · 2014: 3 · 2013: 5 · 2012: 4
- FWCI
- 1.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft (Schu672/14-1, Schu672/10-1, Schu672/12-1, /14-1)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (917-56-358)
- National Heart, Lung, and Blood Institute (HL074321, R01HL074321)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- gp130, atherosclerosis, acute phase proteins, hepatocytes, acute phase response, coronary artery disease, myocardial infarction, plaque macrophages, genetic susceptibility, inflammation, atherosclerotic plaque
- MeSH terms
- Animals, Aorta, Coronary Vessels, Humans, Inflammation, Macrophages, Mice, Inbred C57BL, Polymorphism, Genetic, Risk, Genetic Predisposition to Disease, Hepatocytes, Atherosclerosis, Cytokine Receptor gp130, Mice
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