Modifications of IL-6 by Hypochlorous Acids: Effects on Receptor Binding
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Abstract
High Resolution Image Download MS PowerPoint Slide Interleukin-6 (IL-6) has been implicated in the pathogenesis of inflammatory events including those seen with COVID-19 patients. Positive clinical responses to monoclonal antibodies directed against IL-6 receptors (IL-6Rs) suggest that interference with IL-6-dependent activation of pro-inflammatory pathways offers a useful approach to therapy. We exposed IL-6 to hypochlorous acid (HOCl) in vitro at concentrations reported to develop in vivo . After HOCl treatment, binding of IL-6 to IL-6R was reduced in a dose-dependent manner using a bioassay with human cells engineered to provide a luminescence response to signal transduction upon receptor activation. Similar results followed the exposure of IL-6 to N -chlorotaurine (NCT) and hypobromous acid (HOBr), two other reactive species produced in vivo . SDS-PAGE analysis of HOCl-treated IL-6 showed little to no fragmentation or aggregation up to 1.75 mM HOCl, suggesting that the modifications induced at concentrations below 1.75 mM took place on the intact protein. Mass spectrometry of trypsin-digested fragments identified oxidative changes to two amino acid residues, methionine 161 and tryptophan 157, both of which have been implicated in receptor binding of the cytokine. Our findings suggest that exogenous HOCl and NCT might bring about beneficial effects in the treatment of COVID-19. Further studies on how HOCl and HOBr and their halogenated amine derivatives interact with IL-6 and related cytokines in vivo may open up alternative therapeutic interventions with these compounds in COVID-19 and other hyperinflammatory diseases.
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N-chlorotaurine formation may cause negative regulation of inflammatory processes by multiple distinct molecular mechanisms attenuating NF-kB and related cytokine signaling.
“Importantly, N-chlorotaurine formation may cause the negative regulation of inflammatory processes by multiple distinct molecular mechanisms attenuating NF-kB and related cytokine signaling (88, 116).”
From Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer (2022) · cites this paper as [88]
N-chlorotaurine exposure of IL-6 causes oxidation of residues relevant to IL6R receptor-binding (Met161 and Trp157).
“Indeed, N-chlorotaurine exposure of IL-6 causes oxidation of residues relevant to IL6R receptor-binding (Met161 and Trp157) (88).”
From Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer (2022) · cites this paper as [88]
N-chlorotaurine modulates inflammatory pathologies attributed to chemical modification of inflammatory factors such as IL-6 and NFkB.
“Indeed, it has been shown that N-chlorotaurine modulates inflammatory pathologies attributed to chemical modification of inflammatory factors, such as IL-6 and NFkB.”
From Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer (2022) · cites this paper as [88]
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- Authors
- Robins, L. I., Keim, E. K., Robins, D. B., Edgar, J. S., Meschke, J. S., Gafken, P. R., & Williams, J. F.
- Affiliations
- University of Washington Bothell (US)
- University of Washington (US)
- Issaquah High School, 700 2nd Ave SE, Issaquah, Washington 98027, United States
- Fred Hutch Cancer Center (US)
- Briotech Inc., 14120 NE 200th St, Woodinville, Washington 98072, United States
- Corresponding author
- Robins, Lori I.
- Venue
- ACS Omega
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-12-14
- Volume
- 6
- Issue
- 51
- Pages
- 35593-35599
- ISSN
- 2470-1343 (ISSN-L)
- PMC
- PMC8717532
- OpenAlex
- W4200604636
- Cited by
- 12
- References
- 53
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 1
- FWCI
- 0.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- ACS Omega (publishedVersion, cc-by-nc-nd)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Briotech Incorporated
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- interleukin-6, hypochlorous acid, hypobromous acid, N-chlorotaurine, reactive halogen species, protein oxidation, COVID-19 pandemic, hyperinflammation, monoclonal antibodies
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