ArticlePLoS pathogens2020
SARS-CoV-2 spike protein promotes IL-6 trans-signaling by activation of angiotensin II receptor signaling in epithelial cells.
Article in PLoS pathogens, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 139 papers, 3 of them syntheses that pooled it.
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Who cites it
139 citing papers in PubMed, 3 syntheses or guidelines pooled it, 222 citations in OpenAlex.
- Smoking and vaping alter genes related to mechanisms of SARS-CoV-2 susceptibility and severity: a systematic review and meta-analysis.The European respiratory journal · 2024Pooled it
- Correlation between COVID-19 and hepatitis B: A systematic review.World journal of gastroenterology · 2022Pooled it
- The rationale for the treatment of long-Covid symptoms - A cardiologist's view.Frontiers in cardiovascular medicine · 2022Pooled it
- Blood biomarkers for the prediction of idiopathic taste dysfunction: a case-control study.European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery · 2026Article
- Proteomic analysis identifies pathways related to immune dysregulation in patients with hematologic malignancies after COVID-19 infection.Microbiology spectrum · 2026Article
- Giant Cell Arteritis Following COVID-19 Vaccination: A Consumer-Stimulated Analysis.Drug safety · 2026Article
- Tiliroside From Pavonia malacophylla (Link & Otto) Garcke as an Anti-SARS-CoV-2 Cell Entry Agent.Chemistry & biodiversity · 2026Article
- Differential association of fluticasone furoate and budesonide with clinically detected COVID-19: a retrospective cohort study.BMJ open respiratory research · 2026Article
- Review
- Synthetic messenger RNA vaccines and transcriptomic dysregulation: Evidence from new-onset adverse events and cancers post-vaccination.World journal of experimental medicine · 2025Article
- SARS-CoV2 and Anti-COVID-19 mRNA Vaccines: Is There a Plausible Mechanistic Link with Cancer?Cancers · 2025Review
- Asthma programs the transcriptional response of human nasal epithelial cells to SARS-CoV-2 Spike-mediated ACE2 engagement.The Journal of allergy and clinical immunology · 2025Article
- Network Pharmacology and Experiment Verification-Based Strategy for Exploring the Mechanisms of Shuqing Granule in the Treatment of COVID-19.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Role of NRP1/HDAC4/CREB/RIPK1 Axis in SARS-CoV2 S1 Spike Subunit-Induced Neuronal Toxicity.FASEB bioAdvances · 2025Article
- Review
- Review
- A single-nucleus and spatial transcriptomic atlas of the COVID-19 liver reveals topological, functional, and regenerative organ disruption in patients.Genome biology · 2025Article
- Initial and peak serum levels of Krebs von den Lungen-6 for predicting the prognosis of patients with COVID-19.The Korean journal of internal medicine · 2025Article
- Acute lung injury induced by recombinant SARS-CoV-2 spike protein subunit S1 in mice.Respiratory research · 2025Article
- Characteristics of Oral Adverse Effects following COVID-19 Vaccination and Similarities with Oral Symptoms in COVID-19 Patients: Taste and Saliva Secretory Disorders.Medical principles and practice : international journal of the Kuwait University, Health Science Centre · 2025Review
79 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cytokine storm is suggested as one of the major pathological characteristics of SARS-CoV-2 infection, although the mechanism for initiation of a hyper-inflammatory response, and multi-organ damage from viral infection is poorly understood. In this virus-cell interaction study, we observed that SARS-CoV-2 infection or viral spike protein expression alone inhibited angiotensin converting enzyme-2 (ACE2) receptor protein expression. The spike protein promoted an angiotensin II type 1 receptor (AT1) mediated signaling cascade, induced the transcriptional regulatory molecules NF-κB and AP-1/c-Fos via MAPK activation, and increased IL-6 release. SARS-CoV-2 infected patient sera contained elevated levels of IL-6 and soluble IL-6R. Up-regulated AT1 receptor signaling also influenced the release of extracellular soluble IL-6R by the induction of the ADAM-17 protease. Use of the AT1 receptor antagonist, Candesartan cilexetil, resulted in down-regulation of IL-6/soluble IL-6R release in spike expressing cells. Phosphorylation of STAT3 at the Tyr705 residue plays an important role as a transcriptional inducer for SOCS3 and MCP-1 expression. Further study indicated that inhibition of STAT3 Tyr705 phosphorylation in SARS-CoV-2 infected and viral spike protein expressing epithelial cells did not induce SOCS3 and MCP-1 expression. Introduction of culture supernatant from SARS-CoV-2 spike expressing cells on a model human liver endothelial Cell line (TMNK-1), where transmembrane IL-6R is poorly expressed, resulted in the induction of STAT3 Tyr705 phosphorylation as well as MCP-1 expression. In conclusion, our results indicated that the presence of SARS-CoV-2 spike protein in epithelial cells promotes IL-6 trans-signaling by activation of the AT1 axis to initiate coordination of a hyper-inflammatory response.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.