COVID-19: a new virus, but a familiar receptor and cytokine release syndrome
Open accessAbstract
Zhou et al. (Nature) and Hoffmann et al. (Cell) identify ACE2 as a SARS-CoV-2 receptor, and the latter show its entry mechanism depends on cellular serine protease TMPRSS2. These results may explain proinflammatory cytokine release via the associated angiotestin II pathway and a possible therapeutic target via the IL-6-STAT3 axis.
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The IL-6-STAT3 pathway is now considered a major target for the treatment of inflammatory diseases.
“The IL-6–STAT3 pathway is now considered a major target for the treatment of inflammatory diseases (15, 19, 21, 24–26, 76).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [15]
The Main Text (page unavailable) identifies the IL-6–STAT3 axis as a potential target for cytokine release syndrome in later-stage COVID-19 and links IL-6–STAT3 signaling to inflammatory and autoimmune diseases. It does not establish the pathway as a major treatment target for inflammatory diseases generally; that broader, more definite claim exceeds the paper's qualified proposal. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIL-6 is a major player in chronic inflammatory diseases, autoimmune diseases, cancer and cytokine storm.
“Among them, IL-6 is a major player in chronic inflammatory diseases, autoimmune diseases, cancer and cytokine storm (1, 3, 10–26).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [15]
The Main Text describes the IL-6 amplifier as contributing to inflammatory and autoimmune diseases and discusses IL-6 signaling in COVID-19 cytokine release syndrome. It does not establish IL-6 as a major player in cancer generally; its mention of leukemia and lymphoma concerns cytokine release syndrome following CAR-T therapy. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe IL-6 amplifier plays a key role in inflammatory diseases including cytokine storm syndromes, autoimmune diseases and cancer.
“It too plays a key role in inflammatory diseases including cytokine storm syndromes, autoimmune diseases and cancer (10, 11, 15, 41, 66–68)”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [15]
The Main Text says the IL-6 amplifier can lead to inflammatory and autoimmune diseases. It also proposes a possible role in cytokine release syndrome, rather than establishing a key role. Cancer is mentioned as the condition treated by CAR-T cells, not as a disease in which the IL-6 amplifier plays a key role. (LLM, conf=0.87)
Experimental — accuracy not yet measuredsIL-6Rα is increased in several diseases, indicating that trans-signaling plays important roles in the progression of inflammation in many diseases including severe COVID-19.
“Notably, sIL-6Rα is increased in several diseases, indicating that trans-signaling plays important roles in the progression of inflammation in many diseases including severe COVID-19 (15, 96).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [15]
The Main Text describes formation of sIL-6Rα and IL-6–sIL-6Rα signaling as part of an inflammatory pathway potentially relevant to COVID-19. It does not report that sIL-6Rα is increased in several diseases, and it presents the pathway’s role in COVID-19 as a possibility rather than an established finding. No page number is available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSARS-CoV-1 and SARS-CoV-2 infection activate both NF-κB and STAT3, key elements of the IL-6 Amp, to cause cytokine storm.
“Therefore, SARS-CoV-1 and SARS-CoV-2 infection activate both NF-κB and STAT3, key elements of the IL-6 Amp, to cause cytokine storm (12, 13, 15, 349, 350).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [15]
The Main Text says SARS-CoV-2 infection can activate NF-κB and STAT3 and thereby activate the IL-6 amplifier; it also describes COVID-19 cytokine release syndrome as possibly involving that amplifier. It discusses SARS-CoV-associated ACE2 loss and lung injury, but does not say that SARS-CoV-1 activates both pathways through the IL-6 amplifier. The claim also states the proposed cytokine-storm mechanism more definitively than the source does. Page numbers are not provided in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Severe COVID-19 is a cytokine storm syndrome.
“Consistent with the notion that severe COVID-19 is a cytokine storm syndrome (12–17, 336), the severity of COVID-19 is associated with an increased level of inflammatory cytokines, such as IL-6, granulocyte macrophage colony-stimulating factor (GM-CSF) and TNFα (333, 337).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [15]
ARDS in COVID-19 is considered the result of cytokine storm, resembling the disease caused by SARS-CoV-1 and Middle East respiratory syndrome coronavirus.
“ARDS in COVID-19 is considered the result of cytokine storm (12–17), resembling the disease caused by SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) (335).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [15]
The AngII-AT1R axis is involved in the ARDS induced by SARS-CoV-2 infection, like SARS-CoV-1-induced ARDS in a mouse model.
“Therefore, it is likely that the AngII–AT1R axis is involved in the ARDS induced by SARS-CoV-2 infection (15), which is like SARS-CoV-1-induced ARDS in a mouse model (344).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [15]
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Cites
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Flagged first, then by citations
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Immunology of COVID-19: Current State of the Science
Vabret, N., Britton, G. J., Gruber, C., Hegde, S., Kim, J., Kuksin, M., Levantovsky, R., Malle, L., Moreira, A., Park, M. D., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.05.002 · Cited by 1,623 · see citing works
IL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453 · see citing works
“ARDS in COVID-19 is considered the result of cytokine storm (12–17), re-sembling the disease caused by SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) (335).”
BackgroundInfluentialSelf-citationImmune response, inflammation, and the clinical spectrum of COVID-19
García, L. F. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01441 · Cited by 739 · see citing works
How COVID-19 induces cytokine storm with high mortality
Hojyo, S., Uchida, M., Tanaka, K., Hasebe, R., Tanaka, Y., Murakami, M., & Hirano, T. (2020) · Inflammation and Regeneration · doi:10.1186/s41232-020-00146-3 · Cited by 663 · see citing works
Self-citationCOVID-19 cytokine storm: the anger of inflammation
Mahmudpour, M., Roozbeh, J., Keshavarz, M., Farrokhi, S., & Nabipour, I. (2020) · Cytokine · doi:10.1016/j.cyto.2020.155151 · Cited by 461 · see citing works
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COVID-19 Compared to Other Pandemic Diseases
Pitlik, S. D. (2020) · Rambam Maimonides Medical Journal · doi:10.5041/rmmj.10418 · Cited by 100 · see citing works
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Devaux, C. A., & Camoin-Jau, L. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.1042200 · Cited by 20 · see citing works
- Authors
- Hirano, T., & Murakami, M.
- Affiliations
- Hokkaido University (JP)
- Corresponding author
- Hirano, Toshio
- ORCID
- Murakami, Masaaki
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 52
- Issue
- 5
- Pages
- 731-733
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC7175868
- OpenAlex
- W3019598142
- Cited by
- 772
- References
- 3
- Citations by year
- 2026: 14 · 2025: 36 · 2024: 64 · 2023: 88 · 2022: 158 · 2021: 222 · 2020: 188 · 2018: 2
- FWCI
- 21.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- QST-Repository (National Institutes for Quantum and Radiological Science and Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- Japan Society for the Promotion of Science (20H00502)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- SARS-CoV-2, COVID-19 pandemic, ACE2 receptor, TMPRSS2, viral entry mechanism, cytokine release syndrome, inflammatory cytokines, IL-6/STAT3 signaling, therapeutic target
- MeSH terms
- Betacoronavirus, Cytokine Release Syndrome, COVID-19, SARS-CoV-2, Animals, Chiroptera, Pneumonia, Viral, Coronavirus, Coronavirus Infections, Virus Internalization, Pandemics
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