Redox Modification of Cysteine Residues Regulates the Cytokine Activity of High Mobility Group Box-1 (HMGB1)
Open accessAbstract
High mobility group box 1 (HMGB1) is a nuclear protein with extracellular inflammatory cytokine activity. It is released passively during cell injury and necrosis, and secreted actively by immune cells. HMGB1 contains three conserved redox-sensitive cysteine residues: C23 and C45 can form an intramolecular disulfide bond, whereas C106 is unpaired and is essential for the interaction with Toll-Like Receptor (TLR) 4. However, a comprehensive characterization of the dynamic redox states of each cysteine residue and of their impacts on innate immune responses is lacking. Using tandem mass spectrometric analysis, we now have established that the C106 thiol and the C23-C45 disulfide bond are required for HMGB1 to induce nuclear NF-κB translocation and tumor necrosis factor (TNF) production in macrophages. Both irreversible oxidation to sulphonates and complete reduction to thiols of these cysteines inhibited TNF production markedly. In a proof of concept murine model of hepatic necrosis induced by acetaminophen, during inflammation, the predominant form of serum HMGB1 is the active one, containing a C106 thiol group and a disulfide bond between C23 and C45, whereas the inactive form of HMGB1, containing terminally oxidized cysteines, accumulates during inflammation resolution and hepatic regeneration. These results reveal critical posttranslational redox mechanisms that control the proinflammatory activity of HMGB1 and its inactivation during pathogenesis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
HMGB1 biological activities can switch from pro-inflammatory to anti-inflammatory depending on variables including oxidation state.
“That said, it should be noted that biological activities of HMGB1 may flip from pro-inflammatory to anti-inflammatory depending on multiple variables including its oxidation state [917–923].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [919]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
Antoine, D. J., Williams, D. P., Kipar, A., Laverty, H., & Park, B. K. (2010) · Molecular Medicine · doi:10.2119/molmed.2010.00126 · Cited by 102 · see citing works
Self-citationRetractedRelease of chromatin protein HMGB1 by necrotic cells triggers inflammation
Scaffidi, P., Misteli, T., & Bianchi, M. E. (2002) · Nature · doi:10.1038/nature00858 · Cited by 4,221 · see citing works
Self-citationHMG-1 as a Late Mediator of Endotoxin Lethality in Mice
Wang, H., Bloom, O., Zhang, M., Vishnubhakat, J. M., Ombrellino, M., Che, J., Frazier, A., Yang, H., Ivanova, S., Borovikova, L. V., et al. (1999) · Science · doi:10.1126/science.285.5425.248 · Cited by 3,386 · see citing works
Self-citationAndersson, U., Wang, H., Palmblad, K., Aveberger, A.-C., Bloom, O., Erlandsson-Harris, H., Janson, A., Kokkola, R., Zhang, M., Yang, H., et al. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.4.565 · Cited by 1,401 · see citing works
Self-citationMonocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion
Bonaldi, T., Talamo, F., Scaffidi, P., Ferrera, D., Porto, A., Bachi, A., Rubartelli, A., Agresti, A., & Bianchi, M. E. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg516 · Cited by 1,252 · see citing works
Self-citationEndogenous HMGB1 regulates autophagy
Tang, D., Kang, R., Livesey, K. M., Cheh, C.-W., Farkas, A., Loughran, P., Hoppe, G., Bianchi, M. E., Tracey, K. J., Zeh, H. J., et al. (2010) · Journal of Cell Biology · doi:10.1083/jcb.200911078 · Cited by 951 · see citing works
Self-citationYang, H., Hreggvidsdottir, H. S., Palmblad, K., Wang, H., Ochani, M., Li, J., Lü, B., Chavan, S. S., Rosas‐Ballina, M., Al‐Abed, Y., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1003893107 · Cited by 812 · see citing works
Self-citationCD24 and Siglec-10 Selectively Repress Tissue Damage–Induced Immune Responses
Chen, G.-Y., Tang, J., Zheng, P., & Liu, Y. (2009) · Science · doi:10.1126/science.1168988 · Cited by 786 · cited 1× · see citing works
“Cysteine Redox Characterization of Circulating HMGB1 and Its Association with Hepatic Inflammation during Acetaminophen Hepatotoxicity In Vivo We and others have demonstrated previously that hepatic inflammatory cell recruitment during acetaminophen hepatotoxicity is mediated by HMGB1 (4,13,14).”
Kazama, H., Ricci, J.-E., Herndon, J. M., Hoppe, G., Green, D. R., & Ferguson, T. A. (2008) · Immunity · doi:10.1016/j.immuni.2008.05.013 · Cited by 627 · see citing works
Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox
Rubartelli, A., & Lotze, M. T. (2007) · Trends in Immunology · doi:10.1016/j.it.2007.08.004 · Cited by 614 · see citing works
Specific Recognition of Cruciform DNA by Nuclear Protein HMG1
Bianchi, M. E., Beltrame, M., & Paonessa, G. (1989) · Science · doi:10.1126/science.2922595 · Cited by 611 · see citing works
Self-citationDisulfide bonds as switches for protein function.
Hogg, P. (2003) · TIBS -Trends in Biochemical Sciences. Regular ed · doi:10.1016/s0968-0004(03)00057-4 · Cited by 581 · see citing works
Structural Basis for the Proinflammatory Cytokine Activity of High Mobility Group Box 1
Li, J., Kokkola, R., TABIBZADEH, S. S., Yang, R., Ochani, M., Qiang, X., Harris, H. E., Czura, C. J., Wang, H., Ulloa, L., et al. (2003) · Molecular Medicine · doi:10.1007/bf03402105 · Cited by 371 · see citing works
Self-citationHreggvidsdottir, H. S., Östberg, T., Wähämaa, H., Schierbeck, H., Aveberger, A.-C., Klevenvall, L., Palmblad, K., Ottosson, L., Andersson, U., & Harris, H. E. (2009) · Journal of Leukocyte Biology · doi:10.1189/jlb.0908548 · Cited by 289 · see citing works
Self-citationAntoine, D. J., Williams, D. P., Kipar, A., Jenkins, R. E., Regan, S. L., Sathish, J. G., Kitteringham, N. R., & Park, B. K. (2009) · Toxicological Sciences · doi:10.1093/toxsci/kfp235 · Cited by 223 · see citing works
Self-citationMolecular basis for the redox control of nuclear transport of the structural chromatin protein Hmgb1
Hoppe, G., Talcott, K. E., Bhattacharya, S. K., Crabb, J. W., & Sears, J. E. (2006) · Experimental Cell Research · doi:10.1016/j.yexcr.2006.07.020 · Cited by 191 · see citing works
Recombinant HMGB1 with cytokine-stimulating activity.
Li, J.-H., Wang, H., Mason, J. M., Levine, J., Yu, M., Ulloa, L., Czura, C., Tracey, K., & Yang, H. (2004) · JIM - Journal of Immunological Methods · doi:10.1016/j.jim.2004.04.019 · Cited by 142 · see citing works
Self-citationSchierbeck, H., Lundbäck, P., Palmblad, K., Klevenvall, L., Erlandsson-Harris, H., Andersson, U., & Ottosson, L. (2011) · Molecular Medicine · doi:10.2119/molmed.2010.00264 · Cited by 122 · see citing works
Self-citationStott, K. M., Watson, M. L., Howe, F. S., Grossmann, J. G., & Thomas, J. O. (2010) · Journal of Molecular Biology · doi:10.1016/j.jmb.2010.07.045 · Cited by 116 · see citing works
Redox State-Dependent Interaction of HMGB1 and Cisplatin-Modified DNA
Park, S., & Lippard, S. J. (2011) · Biochemistry · doi:10.1021/bi2000214 · Cited by 74 · see citing works
Protein oxidation: role in signalling and detection by mass spectrometry
Spickett, C. M., & Pitt, A. R. (2012) · Amino Acids · doi:10.1007/s00726-010-0585-4 · Cited by 65 · see citing works
Redox properties of the A‐domain of the HMGB1 protein
Sahu, D., Debnath, P., Takayama, Y., & Iwahara, J. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.09.061 · Cited by 49 · see citing works
Introduction: HMGB1 in inflammation and innate immunity
Andersson, J., & Rauvala, H. (2011) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2011.02430.x · Cited by 48 · see citing works
Redox remodeling: a candidate regulator of HMGB1 function in injured skeletal muscle
Vezzoli, M., Castellani, P., Campana, L., Corna, G., Bosurgi, L., Manfredi, A. A., Bianchi, M. E., Rubartelli, A., & Rovere, P. Q. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05748.x · Cited by 32 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Immunogenic cell death and DAMPs in cancer therapy
Krysko, D. V., Garg, A. D., Kaczmarek, A., Krysko, O., Agostinis, P., & Vandenabeele, P. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3380 · Cited by 3,223 · see citing works
Kang, R., Chen, R., Zhang, Q., Hou, W., Wu, S., Cao, L., Huang, J., Yu, Y., Fan, X.-G., Yan, Z., et al. (2014) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2014.05.001 · Cited by 956 · see citing works
Consensus guidelines for the detection of immunogenic cell death
Kepp, O., Senovilla, L., Vitale, I., Vacchelli, E., Adjemian, S., Agostinis, P., Apetoh, L., Aranda, F., Barnaba, V., Bloy, N., et al. (2014) · OncoImmunology · doi:10.4161/21624011.2014.955691 · Cited by 832 · see citing works
Self-citationMutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release
Venereau, E., Casalgrandi, M., Schiraldi, M., Antoine, D. J., Cattaneo, A., De Marchis, F., Liu, J., Antonelli, A., Preti, A., Raeli, L., et al. (2012) · Journal of Experimental Medicine · doi:10.1084/jem.20120189 · Cited by 720 · see citing works
Self-citationHMGB1: A multifunctional alarmin driving autoimmune and inflammatory disease
Harris, H. E., Andersson, U., & Pisetsky, D. S. (2012) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2011.222 · Cited by 689 · see citing works
Self-citationYang, H., Antoine, D. J., Andersson, U., & Tracey, K. J. (2013) · Journal of Leukocyte Biology · doi:10.1189/jlb.1212662 · Cited by 542 · see citing works
Self-citationp53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes
Davalos, A. R., Kawahara, M., Malhotra, G. K., Schaum, N., Huang, J., Ved, U., Beausejour, C. M., Coppe, J.-P., Rodier, F., & Campisi, J. (2013) · Journal of Cell Biology · doi:10.1083/jcb.201206006 · Cited by 439 · see citing works
HMGB1, IL-1α, IL-33 and S100 proteins: dual-function alarmins
Bertheloot, D., & Latz, E. (2017) · Cellular & Molecular Immunology · doi:10.1038/cmi.2016.34 · Cited by 455 · see citing works
Innate immune signaling and regulation in cancer immunotherapy
Corrales, L., Matson, V., Flood, B., Spranger, S., & Gajewski, T. F. (2017) · Cell Research · doi:10.1038/cr.2016.149 · Cited by 408 · see citing works
The role of neuroimmune signaling in alcoholism
Crews, F. T., Lawrimore, C. J., Walter, T. J., & Coleman, L. G. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.01.031 · Cited by 321 · see citing works
Danger signals in stroke and their role on microglia activation after ischemia
Gülke, E., Gelderblom, M., & Magnus, T. (2018) · Therapeutic Advances in Neurological Disorders · doi:10.1177/1756286418774254 · Cited by 321 · see citing works
Liver regeneration and inflammation: from fundamental science to clinical applications
Campana, L., Esser, H., Huch, M., & Forbes, S. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00373-7 · Cited by 307 · see citing works
Danger-associated molecular patterns in Alzheimer’s disease
Venegas, C., & Heneka, M. T. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.3mr0416-204r · Cited by 236 · see citing works
Weber, M. D., Frank, M. G., Tracey, K. J., Watkins, L. R., & Maier, S. F. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.3561-14.2015 · Cited by 215 · see citing works
Self-citationHigh‐mobility group box‐1 in sterile inflammation
Tsung, A., Tohme, S., & Billiar, T. R. (2014) · Journal of Internal Medicine · doi:10.1111/joim.12276 · Cited by 187 · see citing works
Rabolli, V., Badissi, A. A., Devosse, R., Uwambayinema, F., Yakoub, Y., Palmai-Pallag, M., Lebrun, A., De Gussem, V., Couillin, I., Ryffel, B., et al. (2014) · Particle and Fibre Toxicology · doi:10.1186/s12989-014-0069-x · Cited by 158 · see citing works
Frank, M. G., Weber, M. D., Fonken, L. K., Hershman, S. A., Watkins, L. R., & Maier, S. F. (2016) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2015.10.009 · Cited by 133 · see citing works
Emerging Roles for HMGB1 Protein in Immunity, Inflammation, and Cancer
Ranzato, E., Martinotti, S., & Patrone, M. (2015) · ImmunoTargets and Therapy · doi:10.2147/itt.s58064 · Cited by 127 · see citing works
HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis
Hernandez, C., Huebener, P., Pradere, J.-P., Antoine, D. J., Friedman, R. A., & Schwabe, R. F. (2018) · Journal of Clinical Investigation · doi:10.1172/jci91786 · Cited by 110 · see citing works
Self-citationA Janus Tale of Two Active High Mobility Group Box 1 (HMGB1) Redox States
Tang, D., Billiar, T. R., & Lotze, M. T. (2012) · Molecular Medicine · doi:10.2119/molmed.2012.00314 · Cited by 112 · see citing works
Prantner, D., Nallar, S., & Vogel, S. N. (2020) · The FASEB Journal · doi:10.1096/fj.202002136r · Cited by 92 · see citing works
RAGE Signaling in Skeletal Biology
Plotkin, L. I., Essex, A. L., & Davis, H. M. (2019) · Current Osteoporosis Reports · doi:10.1007/s11914-019-00499-w · Cited by 54 · see citing works
Dear, J. W., & Antoine, D. J. (2014) · Expert Review of Clinical Pharmacology · doi:10.1586/17512433.2014.880650 · Cited by 34 · see citing works
Self-citation
- Authors
- Yang, H., Lundbäck, P., Ottosson, L., Erlandsson-Harris, H., Venereau, E., Bianchi, M. E., Al-Abed, Y., Andersson, U., Tracey, K. J., & Antoine, D. J.
- Affiliations
- Feinstein Institute for Medical Research (US)
- Karolinska University Hospital (SE)
- IRCCS Ospedale San Raffaele (IT)
- University of Liverpool (GB)
- Corresponding author
- Antoine, Daniel J.
- Venue
- Molecular Medicine
- Published
- 2011-11-07
- Volume
- 18
- Issue
- 2
- Pages
- 250-259
- ISSN
- 1076-1551 (ISSN-L)
- 1528-3658
- PMC
- PMC3324950
- OpenAlex
- W1672954108
- Cited by
- 407
- References
- 24
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 12 · 2023: 6 · 2022: 13 · 2021: 16 · 2020: 36 · 2019: 38 · 2018: 34 · 2017: 36 · 2016: 45 · 2015: 37 · 2014: 61 · 2013: 43 · 2012: 23
- FWCI
- 24.50
- Type
- journal article
- Language
- en
- Status
- Retracted
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- creativecommons.org/licenses/by/4.0 (tdm)
- Locations
- Molecular Medicine (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM098446, GM098446, R01GM057226)
- National Center for Research Resources (M01RR018535)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- HMGB1, high mobility group box 1, disulfide bonds, post-translational modification, NF-κB nuclear translocation, TNF-α, macrophages, TLR4, acetaminophen hepatotoxicity, liver necrosis, inflammation resolution, liver regeneration, innate immunity
- MeSH terms
- Acetaminophen, Animals, Cell Line, Cysteine, Humans, Macrophages, Male, Oxidation-Reduction, Tumor Necrosis Factor-alpha, Analgesics, Non-Narcotic, HMGB1 Protein, Mice, Transcription Factor RelA, Chemical and Drug Induced Liver Injury
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
