Neurocritical Care

, 11:362 | Cite as

High-Mobility Group Box 1 Protein in CSF of Patients with Subarachnoid Hemorrhage

  • Takashi Nakahara
  • Ryosuke Tsuruta
  • Tadashi KanekoEmail author
  • Susumu Yamashita
  • Motoki Fujita
  • Shunji Kasaoka
  • Teruto Hashiguchi
  • Michiyasu Suzuki
  • Ikuro Maruyama
  • Tsuyoshi Maekawa



High-mobility group box 1 protein (HMGB1) is a nuclear factor that is a potent proinflammatory mediator, and may trigger increases in other inflammatory cytokines. The inflammatory cytokines in the cerebrospinal fluid (CSF) of patients with subarachnoid hemorrhage (SAH) have been reported previously, but HMGB1 has not. In this study, we measured HMGB1 and the inflammatory cytokines in the CSF of patients with SAH.


CSF samples were collected on days 3, 7, and 14 from the drainage tubes of the postaneurysm clips of 39 patients with SAH. HMGB1, interleukin-6 (IL-6), IL-8, and tumor necrosis factor alpha (TNF-α) were measured in the CSF, and compared between the patients with favorable (good recovery and moderate disability) and unfavorable outcomes (severe disability, vegetative state, and death) at 3 months.


In the unfavorable outcome group, HMGB1 (P = 0.017), IL-6 (P = 0.003), IL-8 (P = 0.041), and TNF-α (P = 0.002) were significantly increased. HMGB1 correlated significantly with IL-6, IL-8, and TNF-α (R = 0.672, 0.421, and 0.697, respectively).


HMGB1 was increased in the CSF of SAH patients with an unfavorable outcome, as were the other cytokines. These results suggest that HMGB1 and cytokines are related to the brain damage observed after SAH. HMGB1 might play a key role in the inflammatory response in the CNS of SAH patients.


HMGB1 Cytokines Subarachnoid hemorrhage Glasgow outcome scale Neuroinflammation 



This clinical study was supported by a research project grant from the Japanese Ministry of Health, Labor, and Welfare (No. H18-trans-general-003). We are grateful to Kiyoshi Ichihara and Yuji Koyanagi (Department of Laboratory Science, Yamaguchi University Graduate School of Medicine) for their valuable statistical assistance, Taku Miyasho (Rakuno Gakuen University) and Hitomi Ikemoto (Yamaguchi University) for their valuable technical assistance with the measurements. We also thank Masako Ueda for assistance with the grant-related paperwork.

Conflict of interest statement

All work was conducted independently of the funding parties, except for a governmental grant. This grant had no influence on the decisions relating to the study design or publication.


  1. 1.
    Anderson UG, Tracey KJ. HMGB1, a pro-inflammatory cytokine of clinical interest. J Intern Med. 2004;255:318–9.CrossRefGoogle Scholar
  2. 2.
    Yan H, Wang H, Czura CJ, Tracey KJ. The cytokine activity of HMGB1. J Leukoc Biol. 2005;78:1–8.CrossRefGoogle Scholar
  3. 3.
    Wang H, Bloom O, Zhang M, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999;285:248–51.CrossRefPubMedGoogle Scholar
  4. 4.
    Mathiesen T, Andersson B, Loftenius A, et al. Increased interleukin-6 levels in cerebrospinal fluid following subarachnoid hemorrhage. J Neurosurg. 1993;78:562–7.CrossRefPubMedGoogle Scholar
  5. 5.
    Kikuchi T, Okuda Y, Kaito N, et al. Cytokine production in cerebrospinal fluid after subarachnoid haemorrhage. Neurol Res. 1995;17:106–8.PubMedGoogle Scholar
  6. 6.
    Gaetani P, Tartara F, Pignatti P, et al. Cisternal CSF levels of cytokines after subarachnoid hemorrhage. Neurol Res. 1998;20:337–42.PubMedGoogle Scholar
  7. 7.
    Osuka K, Suzuki Y, Tanazawa T, et al. Interleukin-6 and development of vasospasm after subarachnoid haemorrhage. Acta Neurochir. 1998;140:943–51.CrossRefGoogle Scholar
  8. 8.
    Hendryk S, Jarzab B, Josko J. Increase of the IL-1 beta and IL-6 levels in CSF in patients with vasospasm following aneurysmal SAH. Neuro Endocrinol Lett. 2004;25:141–7.PubMedGoogle Scholar
  9. 9.
    Takizawa T, Tada T, Kitazawa K, et al. Inflammatory cytokine cascade released by leukocytes in cerebrospinal fluid after subarachnoid hemorrhage. Neurol Res. 2001;23:724–30.CrossRefPubMedGoogle Scholar
  10. 10.
    Oda Y, Tsuruta R, Kasaoka S, Inoue T, Maekawa T. The cutoff values of intrathecal interleukin 8 and 6 for predicting the neurological outcome in cardiac arrest victims. Resuscitation. 2009;80:189–93.CrossRefPubMedGoogle Scholar
  11. 11.
    Wang H, Vishnubhakat JM, Bloom O, et al. Proinflammatory cytokines (tumor necrosis factor and interleukin 1) stimulate release of high mobility group protein-1 by pituicytes. Surgery. 1999;126:389–92.PubMedGoogle Scholar
  12. 12.
    Pullerits R, Jonsson IM, Kollias G, Tarkowski A. Induction of arthritis by high mobility group box chromosomal protein 1 is independent of tumour necrosis factor signaling. Arthritis Res Ther. 2008;10:R72.CrossRefPubMedGoogle Scholar
  13. 13.
    Baumann H, Gauldie J. Acute phase response. Immunol Today. 1994;15:74–80.CrossRefPubMedGoogle Scholar
  14. 14.
    Lennihan L, Mayer SA, Fink ME, et al. Effect of hypervolemic therapy on cerebral blood flow after subarachnoid hemorrhage, a randomized control trial. Stroke. 2000;31:383–91.PubMedGoogle Scholar
  15. 15.
    Yamada S, Inoue K, Yakabe K, Imaizumi H, Maruyama I. High mobility group protein 1 (HMGB1) quantified by ELISA with a monoclonal antibody that does not cross-react with HMGB2. Clin Chem. 2003;49:1535–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Morgan E, Varro R, Sepulveda H, et al. Cytometric bead array: a multiplexed assay platform with applications in various areas of biology. Clin Immunol. 2004;110:252–66.CrossRefPubMedGoogle Scholar
  17. 17.
    Agnello D, Wang H, Yang H, Tracey KL, Ghezzi P. HMGB1, a DNA-binding protein with cytokine activity, induces brain TNF and IL-6 production, and mediates anorexia and taste aversion. Cytokine. 2002;18:231–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Harris HE, Anderson U. The nuclear protein HMGB1 as a proinflammatory mediator. Eur J Immunol. 2004;34:1503–12.CrossRefGoogle Scholar
  19. 19.
    Takata K, Kitamura Y, Tsuchiya D, Kawasaki T, Taniguchi T, Shimohama S. High mobility group box protein-1 inhibits microglial Aβ clearance and enhances Aβ neurotoxicity. J Neurosci Res. 2004;78:880–91.CrossRefPubMedGoogle Scholar
  20. 20.
    Andersson BU, Wang H, Palmblad K, et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med. 2000;192:565–70.CrossRefPubMedGoogle Scholar
  21. 21.
    Randon-Mitchell BR, Ochiai M, Li J, et al. IFN-γ induces high mobility group box 1 protein release partly through a TNF-dependent mechanism. J Immunology. 2003;170:3890–7.Google Scholar
  22. 22.
    Kim JB, Choi JS, Yu YM, et al. HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci. 2006;26:6413–21.CrossRefPubMedGoogle Scholar
  23. 23.
    Mathiesen T, Edner G, Ulfarsson E, Andersson B. Cerebrospinal fluid interleukin-1 receptor antagonist and tumor necrosis factor-α following subarachnoid hemorrhage. J Neurosurg. 1997;87:215–20.CrossRefPubMedGoogle Scholar
  24. 24.
    Faraco G, Fossati S, Bianchi ME, et al. High mobility group box 1 protein is released by neural cells upon different stresses and worsens ischemic neurodegeneration in vitro and in vivo. J Neurochem. 2007;31:1–13.Google Scholar
  25. 25.
    Kimura H, Gules I, Meguro T, Zhang JH. Cytotoxicity of cytokines in cerebral microvascular endotherial cell. Brain Res. 2003;990:148–56.CrossRefPubMedGoogle Scholar
  26. 26.
    Gong Q, Xu JF, Yin H, Liu SF, Duan LH, Bian ZL. Protective effect of antagonist of high-mobility group box 1 on lipopolysaccharide-induced acute lung injury in mice. Scand J Immunol. 2009;69:29–35.CrossRefPubMedGoogle Scholar
  27. 27.
    Tang D, Kang R, Xiao W, et al. Quercetin prevents lipopolysaccharide-induced HMGB1 release and proinflammatory function. Am J Respir Cell Mol Biol 2009 (in press).Google Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Takashi Nakahara
    • 1
  • Ryosuke Tsuruta
    • 1
  • Tadashi Kaneko
    • 1
    Email author
  • Susumu Yamashita
    • 1
  • Motoki Fujita
    • 1
  • Shunji Kasaoka
    • 1
  • Teruto Hashiguchi
    • 2
  • Michiyasu Suzuki
    • 3
  • Ikuro Maruyama
    • 2
  • Tsuyoshi Maekawa
    • 1
  1. 1.Advanced Medical Emergency and Critical Care CenterYamaguchi University HospitalUbeJapan
  2. 2.Department of Laboratory MedicineKagoshima University HospitalKagoshimaJapan
  3. 3.Department of NeurosurgeryYamaguchi University HospitalUbeJapan

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