The extracellular release of HMGB1 during apoptotic cell death
Abstract
High mobility group box 1 protein (HMGB1) is a non-histone nuclear protein with dual function. Inside the cell, HMGB1 binds DNA and regulates transcription, whereas outside the cell, it serves as a cytokine and mediates the late effects of LPS. The movement of HMGB1 into the extracellular space has been demonstrated for macrophages stimulated with LPS as well as cells undergoing necrosis but not apoptosis. The differential release of HMGB1 during death processes could reflect the structure of chromatin in these settings as well as the mechanisms for HMGB1 translocation. Since apoptotic cells can release some nuclear molecules such as DNA to which HMGB1 can bind, we therefore investigated whether HMGB1 release can occur during apoptosis as well as necrosis. For this purpose, Jurkat cells were treated with chemical inducers of apoptosis (staurosporine, etoposide, or camptothecin), and HMGB1 release into the medium was assessed by Western blotting. Results of these experiments indicate that HMGB1 appears in the media of apoptotic Jurkat cells in a time-dependent manner and that this release can be reduced by Z-VAD-fmk. Panc-1 and U937 cells treated with these agents showed similar release. In addition, HeLa cells induced to undergo apoptosis showed HMGB1 release. Furthermore, we showed using confocal microscopy that HMGB1 and DNA change their nuclear location in Jurkat cells undergoing apoptosis. Together, these studies indicate that HMGB1 release can occur during the course of apoptosis as well as necrosis and suggest that the release process may vary with cell type.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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 can be released during secondary necrosis following apoptosis, not only from the nucleus during primary necrosis.
“Although it was initially thought that HMGB1 is released only from the nucleus during primary necrosis, recent data indicate that HMGB1 can be released during secondary necrosis following apoptosis 27,48–50.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [49]
Cites
Release 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
HMG-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
High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal
Lotze, M. T., & Tracey, K. J. (2005) · Nature reviews. Immunology · doi:10.1038/nri1594 · Cited by 2,490 · see citing works
Casciola-Rosen, L. A., Anhalt, G. J., & Rosen, A. (1994) · The Journal of Experimental Medicine · doi:10.1084/jem.179.4.1317 · Cited by 1,723 · see citing works
Andersson, 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
Decker, T., & Lohmann‐Matthes, M. (1988) · Journal of Immunological Methods · doi:10.1016/0022-1759(88)90310-9 · Cited by 1,366 · see citing works
Huynh, M.-L. N., Fadok, V., & Henson, P. (2002) · Journal of Clinical Investigation · doi:10.1172/jci11638 · Cited by 1,333 · see citing works
Monocytic 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
Gardella, S., Andrei, C., Ferrera, D., Lotti, L. V., Torrisi, M. R., Bianchi, M. E., & Rubartelli, A. (2002) · EMBO Reports · doi:10.1093/embo-reports/kvf198 · Cited by 926 · see citing works
Cutting Edge: HMG-1 as a Mediator of Acute Lung Inflammation
Abraham, E. H., Arcaroli, J. J., Carmody, A., Wang, H., & Tracey, K. J. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.6.2950 · Cited by 692 · see citing works
HMGB1 is an endogenous immune adjuvant released by necrotic cells
Rovere, P. Q., Capobianco, A., Scaffidi, P., Valentinis, B., Catalanotti, F., Giazzon, M., Dumitriu, I. E., Müller, S., Iannacone, M., Traversari, C., et al. (2004) · EMBO Reports · doi:10.1038/sj.embor.7400205 · Cited by 591 · see citing works
Lamin proteolysis facilitates nuclear events during apoptosis.
Rao, L., Perez, D., & White, E. (1996) · The Journal of Cell Biology · doi:10.1083/jcb.135.6.1441 · Cited by 586 · see citing works
The cytokine activity of HMGB1
Yang, H., Wang, H., Czura, C. J., & Tracey, K. J. (2005) · Journal of Leukocyte Biology · doi:10.1189/jlb.1104648 · Cited by 545 · see citing works
Earnshaw, W. C. (1995) · Current Opinion in Cell Biology · doi:10.1016/0955-0674(95)80088-3 · Cited by 534 · see citing works
Cleavage by Granzyme B Is Strongly Predictive of Autoantigen Status
Casciola-Rosen, L. A., Andrade, F., Ulanet, D., Wong, W. B., & Rosen, A. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.190.6.815 · Cited by 492 · see citing works
Müller, S., Ronfani, L., & Bianchi, M. E. (2004) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2003.01296.x · Cited by 368 · see citing works
McDonald, P. P., Fadok, V. A., Bratton, D. L., & Henson, P. M. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.163.11.6164 · Cited by 350 · see citing works
Apoptosis: The importance of being eaten
Ren, Y., & Savill, J. (1998) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400407 · Cited by 347 · see citing works
Rapid and Specific Efflux of Reduced Glutathione during Apoptosis Induced by Anti-Fas/APO-1 Antibody
van den Dobbelsteen, D. J., Nobel, S., Schlegel, J., Cotgreave, I. A., Orrenius, S., & Slater, A. F. G. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.26.15420 · Cited by 343 · see citing works
HMGB1: guiding immunity from within
Dumitriu, I. E., Baruah, P., Manfredi, A. A., Bianchi, M. E., & Rovere, P. Q. (2005) · Trends in Immunology · doi:10.1016/j.it.2005.04.009 · Cited by 340 · see citing works
IFN-γ Induces High Mobility Group Box 1 Protein Release Partly Through a TNF-Dependent Mechanism
Rendon-Mitchell, B., Ochani, M., Li, J., Han, J., Wang, H., Yang, H., Susarla, S. M., Czura, C. J., Mitchell, R. A., Chen, G., et al. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.7.3890 · Cited by 337 · see citing works
McDonald, P. P., Fadok, V. A., Bratton, D. L., & Henson, P. M. (1999) · PubMed · Cited by 332 · see citing works
HMGB1 as a DNA-binding cytokine
Andersson, U., Erlandsson-Harris, H., Yang, H., & Tracey, K. J. (2002) · Journal of Leukocyte Biology · doi:10.1189/jlb.72.6.1084 · Cited by 302 · see citing works
Caspases Disrupt the Nuclear-Cytoplasmic Barrier
Faleiro, L. J., & Lazebnik, Y. A. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.151.5.951 · Cited by 248 · see citing works
Comparison of Cell Proliferation and Toxicity Assays Using Two Cationic Liposomes
Lappalainen, K., Jääskeläinen, I., Syrjänen, K. J., Urtti, A. O., & Syrjänen, S. (1994) · Pharmaceutical Research · doi:10.1023/a:1018932714745 · Cited by 238 · see citing works
Neamati, N., Fernandez, A., Wright, S. J., Kiefer, J., & McConkey, D. J. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.154.8.3788 · Cited by 237 · see citing works
Parkkinen, J., Raulo, E., Merenmies, J. M., Nolo, R. M., Kajander, E. O., Baumann, M., & Rauvala, H. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)36575-5 · Cited by 216 · see citing works
Choi, J., Reich, C. F., & Pisetsky, D. S. (2005) · Immunology · doi:10.1111/j.1365-2567.2005.02130.x · Cited by 199 · see citing works
Self-citationChen, G., Li, J., Ochani, M., Rendon-Mitchell, B., Qiang, X., Susarla, S. M., Ulloa, L., Yang, H., Fan, S., Goyert, S. M., et al. (2004) · Journal of Leukocyte Biology · doi:10.1189/jlb.0404242 · Cited by 188 · see citing works
Rapid extracellular release of cytochrome c is specific for apoptosis and marks cell death in vivo
Renz, A., Berdel, W. E., Kreuter, M., Belka, C., Schulze‐Osthoff, K., & Łoś, M. (2001) · Blood · doi:10.1182/blood.v98.5.1542 · Cited by 178 · see citing works
Extracellular Tyrosinase mRNA within Apoptotic Bodies Is Protected from Degradation in Human Serum
Hasselmann, D. O., Rappl, G., Tilgen, W., et al. (2001) · Clinical Chemistry · doi:10.1093/clinchem/47.8.1488 · Cited by 173 · see citing works
Zeh, H. J., & Lotze, M. T. (2004) · Journal of Immunotherapy · doi:10.1097/00002371-200501000-00001 · Cited by 164 · see citing works
Popovic, K., Ek, M., Espinosa, A., Padyukov, L., Harris, H. E., Wahren‐Herlenius, M., & Nyberg, F. (2005) · Arthritis & Rheumatism · doi:10.1002/art.21398 · Cited by 140 · see citing works
Antibodies against chromosomal HMG proteins stain the cytoplasm of mammalian cells
Bustin, M., & Neihart, N. K. (1979) · Cell · doi:10.1016/0092-8674(79)90199-5 · Cited by 139 · see citing works
Measurement of an apoptotic product in the sera of breast cancer patients
Ueno, T., Toi, M., Bivén, K., Bando, H., Ogawa, T., & Linder, S. T. (2003) · European Journal of Cancer · doi:10.1016/s0959-8049(02)00865-1 · Cited by 127 · see citing works
Bianchi, M. E., & Manfredi, A. A. (2003) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/j.bbaexp.2003.10.017 · Cited by 123 · see citing works
Release of DNA from Dead and Dying Lymphocyte and Monocyte Cell Lines In Vitro
Choi, J. ‐., Reich, C. F., & Pisetsky, D. S. (2004) · Scandinavian Journal of Immunology · doi:10.1111/j.0300-9475.2004.01470.x · Cited by 97 · see citing works
Self-citationRole of macrophages in the generation of circulating blood nucleosomes from dead and dying cells
Jiang, N., Reich, C. F., & Pisetsky, D. S. (2003) · Blood · doi:10.1182/blood-2002-10-3312 · Cited by 94 · see citing works
Self-citationCondensation of vector DNA by the chromosomal protein HMG1 results in efficient transfection
Böttger, M., Vogel, F., Platzer, M., Kiessling, U., Grade, K., & Strauss, M. (1988) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/0167-4781(88)90014-0 · Cited by 61 · see citing works
Nuclear RNA Is Extruded from Apoptotic Cells
Biggiogera, M., Bottone, M. G., & Pellicciari, C. (1998) · Journal of Histochemistry & Cytochemistry · doi:10.1177/002215549804600903 · Cited by 59 · see citing works
Bianchi, M. E. (2004) · Trends in Cell Biology · doi:10.1016/j.tcb.2004.04.004 · Cited by 54 · see citing works
Caspase-3 activity is present in cerebrospinal fluid from patients with traumatic brain injury
Härter, L., Keel, M. J. B., Hentze, H., Leist, M., & Ertel, W. (2001) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(01)00409-x · Cited by 52 · see citing works
Leukocyte circulation: one-way or round-trip? Lessons from primary immunodeficiency patients
Badolato, R. (2004) · Journal of Leukocyte Biology · doi:10.1189/jlb.1103529 · Cited by 52 · see citing works
Li, C., Hsu, H., Wu, T., Tsao, K., Sun, C., & Wu, J. T. (2003) · Journal of Clinical Laboratory Analysis · doi:10.1002/jcla.10081 · Cited by 51 · see citing works
Isackson, P. J., Bidney, D. L., Reeck, G. R., Neihart, N. K., & Bustin, M. (1980) · Biochemistry · doi:10.1021/bi00560a013 · Cited by 46 · see citing works
The expression of plasma nucleosomes in mice undergoing in vivo apoptosis
Jiang, N., Reich, C. F., Monestier, M., et al. (2003) · Clinical Immunology · doi:10.1016/s1521-6616(02)00027-x · Cited by 38 · see citing works
Self-citationAnker, P., & Stroun, M. (2002) · Clinical Chemistry · doi:10.1093/clinchem/48.8.1210 · Cited by 36 · see citing works
Mechanisms of activation of the RAW264.7 macrophage cell line by transfected mammalian DNA
Jiang, W., Reich, C. F., & Pisetsky, D. S. (2004) · Cellular Immunology · doi:10.1016/j.cellimm.2004.06.003 · Cited by 33 · see citing works
Self-citationDNA as a marker of cell death in systemic lupus erythematosus
Pisetsky, D. S. (2004) · Rheumatic Disease Clinics of North America · doi:10.1016/j.rdc.2004.04.009 · Cited by 26 · see citing works
Self-citationThe Effect of Dexamethasone on the Generation of Plasma DNA from Dead and Dying Cells
Jiang, N., & Pisetsky, D. S. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63733-9 · Cited by 15 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
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
Immunogenic and tolerogenic cell death
Green, D. R., Ferguson, T., Zitvogel, L., & Kroemer, G. (2009) · Nature Reviews Immunology · doi:10.1038/nri2545 · Cited by 1,176 · see citing works
HMGB1: 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-citationKazama, 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
High‐mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity
Bianchi, M. E., & Manfredi, A. A. (2007) · Immunological Reviews · doi:10.1111/j.1600-065x.2007.00574.x · Cited by 600 · see citing works
Yang, 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
HMGB1 release and redox regulates autophagy and apoptosis in cancer cells
Tang, D., Kang, R., Cheh, C.-W., Livesey, K. M., Liang, X., Schapiro, N. E., Benschop, R., Sparvero, L. J., Amoscato, A. A., Tracey, K. J., et al. (2010) · Oncogene · doi:10.1038/onc.2010.261 · Cited by 461 · 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
Targeting HMGB1 in inflammation
Yang, H., & Tracey, K. J. (2010) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2009.11.019 · Cited by 351 · see citing works
Autophagy regulates selective HMGB1 release in tumor cells that are destined to die
Thorburn, J., Horita, H., Redzic, J., Hansen, K., Frankel, A. E., & Thorburn, A. (2009) · Cell Death & Differentiation · doi:10.1038/cdd.2008.143 · Cited by 268 · see citing works
High‐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
Jiang, W., Bell, C. W., & Pisetsky, D. S. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.10.6495 · Cited by 134 · see citing works
Self-citationZhai, J., Gu, X., Liu, Y., Hu, Y., Jiang, Y., & Zhang, Z. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1152934 · Cited by 131 · 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 is a bone‐active cytokine
Yang, J., Shah, R., Robling, A. G., Templeton, E., Yang, H., Tracey, K. J., & Bidwell, J. P. (2008) · Journal of Cellular Physiology · doi:10.1002/jcp.21268 · Cited by 97 · see citing works
Cheng, M., Liu, H., Zhang, D., Liu, Y., Wang, C., Liu, F., & Chen, J. (2015) · American Journal of Nephrology · doi:10.1159/000381464 · Cited by 66 · see citing works
Vaz, A. R., Pinto, S., Ezequiel, C., Cunha, C., Carvalho, L. A., Moreira, R., & Brites, D. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00109 · Cited by 55 · see citing works
- Authors
- Bell, C. W., Jiang, W., Reich, C. F., & Pisetsky, D. S.
- Affiliations
- Duke Medical Center (US)
- ORCID
- Pisetsky, David S.
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2006-12
- Volume
- 291
- Issue
- 6
- Pages
- C1318-C1325
- ISSN
- 0363-6143 (ISSN-L)
- 1522-1563
- OpenAlex
- W2166495164
- Cited by
- 538
- References
- 50
- Citations by year
- 2026: 15 · 2025: 15 · 2024: 19 · 2023: 21 · 2022: 25 · 2021: 26 · 2020: 21 · 2019: 18 · 2018: 22 · 2017: 19 · 2016: 25 · 2015: 37 · 2014: 35 · 2013: 44 · 2012: 32
- FWCI
- 17.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Cell Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI44808)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- HMGB1, extracellular HMGB1 release, apoptosis, necrosis, HMGB1 translocation, Jurkat cells, staurosporine, etoposide, camptothecin, z-VAD-fmk, chromatin structure, cell death
- MeSH terms
- Amino Acid Chloromethyl Ketones, Antineoplastic Agents, Phytogenic, Camptothecin, Cell Line, Cycloheximide, Enzyme Inhibitors, Etoposide, Humans, Hydroxamic Acids, Protein Synthesis Inhibitors, Tumor Necrosis Factor-alpha, Cysteine Proteinase Inhibitors, Apoptosis, Staurosporine, HMGB1 Protein
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
