Originally published online as doi:10.1189/jlb.1104648 on February 25, 2005
Published online before print February 25, 2005
(Journal of Leukocyte Biology. 2005;78:1-8.)
© 2005
by Society for Leukocyte Biology
The cytokine activity of HMGB1
Huan Yang1,
Haichao Wang,
Christopher J. Czura and
Kevin J. Tracey
Laboratory of Biomedical Science, Institute for Medical Research at North Shore-Long Island Jewish Health System, Manhasset, New York
1 Correspondence: Laboratory of Biomedical Science, Institute for Medical Research at North Shore-Long Island Jewish System, 350 Community Drive, Manhasset, NY 11030. E-mail: hyang{at}nshs.edu
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ABSTRACT
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High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein present in the nuclei and cytoplasm of nearly all cell types. We recently discovered that HMGB1 is secreted into the extracellular milieu and acts as a proinflammatory cytokine. Administration of HMGB1 to normal animals causes inflammatory responses, including fever, weight loss and anorexia, acute lung injury, epithelial barrier dysfunction, arthritis, and death. Anti-HMGB1 treatment, with antibodies or specific antagonists, rescues mice from lethal endotoxemia or sepsis and ameliorates the severity of collagen-induced arthritis and endotoxin-induced lung injury. Here, we give an abridged review of the cytokine activity of HMGB1, its secretion and release into the extracellular milieu, the putative signal transduction pathways, including interaction with cell-surface receptors and intracellular signaling, and its role in several inflammatory diseases. Finally, the therapeutic potential of blocking HMGB1 in the treatment of inflammatory diseases is discussed.
Key Words: TNF • inflammation • sepsis
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INTRODUCTION
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Sepsis is a systemic, inflammatory response to infection and is associated with diffuse coagulation, multiple organ failure, and death. The mortality rate from severe sepsis remains over 30%, despite advances in intensive care therapy; accordingly, the annual health care cost associated with this diagnosis is as high as $16.7 billion per year [1
, 2
]. Previous work in the pathogenesis of sepsis has highlighted the importance of proinflammatory mediators in the course of sepsis. Despite success in animals [3
4
5
6
], clinical trials inhibiting the early cytokine mediators [i.e., tumor necrosis factor (TNF) or interleukin (IL)-1] have failed to improve survival in septic patients [5
, 6
]. An alternative approach is to target other later mediators of sepsis to provide a wider window of opportunity for the treatment of this lethal syndrome.
We initiated a program to search for putative, "late" mediators in sepsis. Our research has resulted in the identification of high mobility group box 1 (HMGB1) as a late mediator in endotoxemia and sepsis [7
, 8
]. Previously, HMGB1 was known as an abundant protein present in nuclei and cytoplasm and involved in maintaining nucleosome structure and regulation of gene transcription [9
]. We found that once released into the extracellular milieu, HMGB1 activates inflammatory responses. This recent discovery of the extracellular role of HMGB1 as a proinflammatory cytokine has opened up a new field of research to study the role of HMGB1 in inflammatory diseases, including severe sepsis and arthritis. HMGB1 is unique in its delayed release kinetics, suggesting that it may be an important therapeutic target in lethal systemic inflammatory diseases in which excessive amounts of HMGB1 are released. HMGB1 is found in the synovium of arthritic joints of humans, and specific inhibition of HMGB1 activity attenuates the development of murine experimental arthritis. These and other observations indicate that HMGB1 is an important mediator of local and systemic inflammatory diseases.
Cytokines have been defined as proteins that can be released from activated immunocytes and mediate diverse metabolic and immunological responses in other cells [10
]. Several laboratories have demonstrated independently that HMGB1, a ubiquitous and chromosomal protein, can be actively released from a variety of cells including macrophage-like RAW 264.7 cells [7
], pituicytes [11
], human primary peripheral blood mononuclear cells [12
], and murine erythroleukemia cells[13
]. Once released, HMGB1 can bind to cell-surface receptors [e.g., the receptor for advanced glycation end products (RAGE), Toll-like receptor (TLR)2, and TLR4] and mediate various cellular responses including chemotactic cell movement and release of proinflammatory cytokines (e.g., TNF and IL-1) [12
, 14
15
16
17
]. Taken together, these observations characterize HMGB1 as a nonclassical, proinflammatory cytokine.
This review summarizes the recent advances on the cytokine role of HMGB1 in inflammatory diseases, its secretion and release into the extracellular milieu, and its putative signal transduction pathways, including interaction with cell-surface receptors and intracellular signaling. Finally, the therapeutic potential of blocking HMGB1 in the treatment of inflammatory diseases is discussed.
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GENE, STRUCTURE, AND TISSUE DISTRIBUTIONS OF HMGB1
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HMGB1 (previously known as HMG-1 or amphoterin [18
]) was first discovered as an abundant nuclear protein over 30 years ago [9
]. The human HMGB1 gene is located on chromosome 13q12 and encodes a protein of 216 amino acids [19
20
21
]. Southern blot analysis of human genomic DNA reveals several bands, suggesting multiple genes or pseudo-genes within the genome [21
]. HMGB1 is highly conserved among species, with over 98% sequence identity between rodents and humans [22
23
24
]. Structurally, HMGB1 is composed of three domains: two homologous DNA-binding motifs, A box and B box, and a negatively charged C terminus (acidic tail; Fig. 1
) [25
, 26
]. HMGB1 is a ubiquitous protein and is widely distributed in all mammalian tissues [27
, 28
]. HMGB1-like proteins are also found in yeast, bacteria, and plants [28
]. The cellular localization of HMGB1 is tissue-specific with high levels found in the thymus, lymphoid tissues, testis, and neonatal livers. Intracellularly, HMGB1 is more concentrated in the cytoplasm of cells in liver and brain, and is concentrated in the nuclei in most other tissues (Fig. 1)
[29
].
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Figure 1. HMGB1 gene, structure, and expression. (Upper) Human HMGB1 is composed of three domains: two homologous DNA-binding domains, A and B boxes, and a negatively charged C terminus (Acidic tail). (Lower) Expression of HMGB1 in different species and tissue distribution.
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HMGB1 AS A DNA-BINDING PROTEIN
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Previously, HMGB1 has been widely studied as a nuclear DNA-binding protein, which participates in maintaining nucleosome structure, regulation of gene transcription [30
], and modulating the activity of steroid hormone receptors [31
, 32
]. HMGB1-deficient mice die shortly after birth, possibly as a result of a defect in activation of glucocorticoid receptor-responsive genes, further supporting the important role of HMGB1 in regulation of gene transcription [33
].
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HMGB1 SECRETION
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HMGB1 does not contain a signal sequence and thus, does not traverse the endoplasmic reticulum/Golgi system, but it is released into the extracellular milieu actively by various cells (activated macrophages/monocytes, pituicytes, and erythroleukemia cells) or passively by necrotic or damaged cells (Fig. 2
) [7
, 11
, 34
, 35
]. For example, cultured macrophages/monocytes or pituicytes stimulated with LPS or proinflammatory cytokines (i.e., TNF, IL-1ß, and IFN-
) actively secrete HMGB1, with detectable accumulation 8 h after stimulation [7
, 11
, 34
]. The release of leaderless cytokines is not unique to HMGB1, as fibroblast growth factor and IL-1ß are also actively released without a consensus leader sequence [36
, 37
]. Immunofluorescent analyses indicate that stimulation of macrophages/monocytes with LPS or TNF induces HMGB1 translocation from the nucleus to cytoplasmic organelles (Fig. 2)
[34
, 38
, 39
]. Moreover, Bonaldi et al. [40
] recently showed that hyperacetylated HMGB1, induced by stimulation with LPS or forced hyperacetylation by acetylases in resting macrophages, relocates HMGB1 from nuclei to cytosol toward secretion (Fig. 2)
.
In addition to active release from macrophages/monocytes, HMGB1 can be passively released by necrotic or damaged cells when the integrity of cytoplasmic membranes is broken (Fig. 2)
[35
]. Necrotic cells deficient in HMGB1 have diminished ability to induce inflammatory responses compared with wild-type cells [35
]. Apoptotic cells do not release significant quantities of HMGB1, as these cells retain HMGB1 within their nuclei, even when the integrity of their membranes is lost; these cells do not trigger inflammation. These data indicate that HMGB1 is a critical stimulus of inflammation at the site of cell injury and death.
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HMGB1 RECEPTOR(S) AND INTRACELLULAR SIGNALING
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RAGE is a transmembrane protein and a member of the immunoglobulin superfamily. RAGE is expressed in endothelial cells, vascular smooth muscle cells, neurons, and macrophages/monocytes [14
]. As a receptor of multiple ligands, RAGE has also been implicated as a receptor mediating the cytokine activity of HMGB1 in macrophages and tumor cells [14
, 41
42
43
44
]. Membrane-associated HMGB1 induces neurite outgrowth by interaction with RAGE [45
, 46
]. In cultured embryonic rat neurons, radioligand-binding studies with 125I-HMGB1 reveals that the binding affinity of HMGB1 to RAGE is sevenfold higher than to advanced glycation end-products, the first identified ligand for RAGE [45
]. Interaction of RAGE with ligand (including HMGB1) has two main consequences: One activates CDC42 and Rac, guanosine triphosphatases that regulate cell motility and neurite outgrowth, and the other pathway activates several mitogen-activated protein kinases (MAPKs) and subsequently leads to activation of nuclear factor (NF)-
B (Fig. 3
) [47
]. Interaction of RAGE and HMGB1 causes phosphorylation of MAPKs (e.g., p38 and p42/44 kinases, stress-activated protein kinase/c-Jun N-terminal kinase, ERK1/2) and activation of the NF-B signaling pathway in cultured macrophages, neutrophils, and Caco-2 epithelial cells [47
48
49
]. Moreover, HMGB1-mediated smooth muscle cell migration also involves activation of MAPK pathways and a G-protein-coupled receptor [17
].
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Figure 3. HMGB1 signal transduction pathways. HMGB1 binds RAGE, TLR2, and possibly TLR4 and other receptors. Activation of RAGE has two main consequences: One activates CDC42 and Rac, which regulate neurite outgrowth during neuron development, and the other activates Ras, MAPK pathways, and subsequently, NF-B nuclear translocation. Activation of TLR2 (and/or TLR4) by HMGB1 causes recruiting MyD88 and IL-1 receptor-associated kinase (IRAK), subsequently activates MAPK pathway and NF-B translocation, and triggers inflammatory responses. Erk1/2, Extracellular signal-regulated kinase 1/2.
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Recent structure-functional analyses revealed that HMGB1 amino acid residues 150–183 are responsible for RAGE binding [47
]. However, evidence suggests that RAGE alone could not explain all the effects of HMGB1, as discrepancies exist between specific HMGB1-binding/RAGE activation and biological effects of HMGB1. First, structure-functional analysis has shown that HMGB1 B box, a DNA-binding domain of HMGB1, acts as the proinflammatory cytokine domain of HMGB1, but it does not contain the RAGE-binding sequence [48
, 50
]. Second, several groups have shown that anti-RAGE antibody only partially inhibits HMGB1-mediated cytokine activity (refs. [48
, 50
51
] and our unpublished data). Third, Li et al. [52
] observed that necrotic cells stimulated NF-B activation in macrophages, and this process is via a TLR2-dependent pathway. Last, we recently have shown that HMGB1 can signal through TLR2 [15
]. Using human embryonic kidney cells overexpressing TLR2 or TLR4, we found that HMGB1 induces IL-8 release only from TLR2-overexpressing cells and not from TLR4 or control vector-overexpressing cells. These effects are not likely to be a result of contaminating bacterial TLR2 or TLR4 agonists, as the LPS content in HMGB1 preparations is consistently less than 3 pg/µg protein after purification with Triton X-114 [53
]. Furthermore, no bacterial TLR2 agonists (peptidoglycan-associated lipoprotein, antimurein lipoprotein, outer membrane protein A) were detected in HMGB1 proteins (our unpublished data). Recent data indicate that TLR4 may also play a role in HMGB1 signaling (Fig. 3)
[16
]. Although the interaction of RAGE, TLR2, and TLR4 and the relative contributions of different receptors to HMGB1 signaling are still under investigation, results to date indicate that RAGE and members of the TLRs are important receptors in HMGB1 signaling.
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HMGB1 ACTIVATES THE INFLAMMATORY SYSTEM IN VITRO
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The cytokine activity of HMGB1 has been well-documented in many cell types (Table 1
).
Macrophage/monocyte
In cultured human primary macrophages/monocytes, HMGB1 is potent in stimulating the release of multiple proinflammatory cytokines, including TNF, IL-1
, IL-1ß, IL-1RA, IL-6, IL-8, MIP-1, and MIP-1ß, but not IL-10 and IL-12 [12
]. The kinetics of HMGB1- or LPS-induced TNF release is notably different, as HMGB1 induces TNF release significantly later than LPS, which induces the release of TNF in a single peak 2–3 h after stimulation, whereas HMGB1 induces a biphasic TNF response, with the first peak at approximately 3 h and a second peak 8–10 h after HMGB1 exposure.
Endothelium
In cultured human microvascular endothelial cells, addition of HMGB1 induces the expression of adhesion molecules such as ICAM-1, VCAM-1, and RAGE, as well as release of TNF and IL-8, MCP-1, PAI-1, and tPA [51
]. Treutiger et al. [65
] confirmed these findings in cultured human umbilical venular endothelial cells and further showed that HMGB1 and the inflammatory domain HMGB1 B box mediate inflammatory responses in endothelial cells. HMGB1 also disrupts the barrier function of endothelial monolayers [66
]. These findings indicate that HMGB1 is capable of promoting inflammatory responses in the endothelium during infection and tissue injury.
Neutrophil
HMGB1 also activates human neutrophils to produce proinflammatory mediators such as TNF, IL-1ß, and IL-8, suggesting an important role of HMGB1 in activation of neutrophils during inflammation [49
].
Epithelium
HMGB1 and B box, a proinflammatory domain of HMGB1, increase the permeability in cultured enterocytes via a nitric oxide (NO)-dependent pathway [48
, 50
].
Dendritic cell
More recently, HMGB1 and B box have been shown to have activity as an immunostimulatory signal, which induces dendritic cell maturation and secretion of proinflammatory cytokines including TNF, IL-1, IL-6, IL-8, and IL-12 [54
]. B box also induced phenotypic maturation of dendritic cells, as evidenced by increased expression of CD40, CD54, CD58, CD80, and CD83, suggesting that extracellular HMGB1, when sensed by dendritic cells, may induce and/or enhance antigen presentation [54
, 55
].
Smooth muscle cells
HMGB1 acts as a strong chemotatic agent for smooth muscle cells, causing their migration from tunica to intima, implicating HMGB1-induced pathology in vascular diseases such as atherosclerosis and restenosis [17
, 56
].
Others
HMGB1 induces migration and proliferation in adult and embryonic vessel-associated stem cells (mesoangioblasts) [66
]. HMGB1 inhibits apoptosis induced by the proapoptotic Bcl-2 family member Bak in yeast Schizosaccharomyces pombe and in mammalian cells [67
].
Collectively, these results indicate that HMGB1 can promote effective, inflammatory responses in various cell types.
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HMGB1 CAUSES INFLAMMATORY RESPONSES IN VARIOUS ORGAN SYSTEMS IN VIVO
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Brain
Intracerebrocentricular administration of HMGB1 increases brain TNF, IL-1, and IL-6 expression and induces sickness behaviors such as fever, anorexia, taste aversion, and weight loss in mice, indicating that HMGB1 has proinflammatory characteristics in the central nervous system [57
, 58
].
Lung
Elevated HMGB1 levels were found in plasma and lung epithelial lining fluid of patients with acute lung injury and in mice instilled with LPS [59
]. Addition of HMGB1 intratracheally in mice causes acute lung injury as manifested by neutrophil accumulation, lung edema, and increased pulmonary cytokine levels, including TNF, IL-1ß, and MIP-2 [60
]. Treatment with anti-HMGB1 antibodies in mice exposed to intratracheal LPS significantly decreases lung edema and neutrophil accumulation but does not suppress LPS-induced pulmonary cytokines, indicating an important role of HMGB1 in acute lung injury [59
60
61
].
Gastrointestinal tract
HMGB1 and B box impair intestinal barrier function in mice and increase ileal mucosa permeability and bacterial translocation to mesenteric lymph nodes. This impairment is via a mechanism that depends on NO formation [48
].
Joints
Biopsy samples from rheumatoid arthritis patients showed elevated HMGB1 levels in synovial fluid [39
, 68
]. Similarly, high levels of HMGB1 have been observed in adjuvant arthritis in rats [68
]. Immunostaining of synovial tissues from adjuvant-induced arthritis rats showed that HMGB1 is abundantly expressed as a nuclear, cytoplasmic, and extracellular component, compared with specimens from normal rats, in which HMGB1 is primarily confined to the nucleus [68
]. Intra-articular administration of HMGB1 induces the onset of arthritis in mice [62
], suggesting an important role of HMGB1 in the pathogenesis of arthritis [69
, 70
].
Heart
HMGB1 has been found to cause arrhythmia in rodents (our unpublished observation).
Prokaryotes
HMGB1 is toxic to bacteria as a result of its acidic tail [63
]. Recent studies showed that HMGB1 mediates strong and direct bactericidal effects against the airway pathogen Moraxella catarrhalis and Escherichia coli. HMGB1 eradicated more than 95% of bacteria in cell cultures within 5 min [64
].
Taken together, these results show that the beneficial antibacterial activity of HMGB1 is integrated to its role as a potent, proinflammatory cytokine, that orchestrates a cascade of injurious, inflammatory responses, and induces a broad spectrum of systemic changes in various systems in vitro and in vivo (our recent review, ref. [71
]; Table 1
and Fig. 4
).
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Figure 4. The inflammatory cascade triggered by HMGB1, which activates inflammatory responses through multiple pathways including macrophage activation and release of proinflammatory cytokines; endothelial cell activation and increased expression of adhesion molecules; increased expression of PAI-1 and tPA, which are involved in regulation of coagulation; and increased epithelial permeability and bacterial translation in the gut. These pathways lead to a cascade of inflammatory responses that can cause tissue damage and even death.
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ROLE OF HMGB1 IN SYSTEMIC AND LOCAL INFLAMMATION
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Endotoxemia and sepsis
HMGB1 is released systemically in murine models of endotoxemia and sepsis induced by cecal perforation [7
, 8
]. The kinetics of HMGB1 release is delayed compared with most other cytokines. Serum HMGB1 levels remain unchanged during the first 8 h after injection of a 50% lethal dose of LPS in mice but increase significantly after 16 h and stay at elevated plateau levels for at least 36 h [7
]. A similar pattern of HMGB1 release is observed in a standardized murine sepsis model induced by cecal perforation [8
]. This delayed HMGB1 response is different from TNF and distinguishes HMGB1 from other early-acting, proinflammatory cytokines [44
]. Furthermore, serum HMGB1 levels were significantly increased in 25 sepsis patients compared with healthy volunteers, and levels were found higher in patients succumbed to the disease than in survivors [7
].
Hemorrhagic shock
Hemorrhagic shock, like septic shock, is characterized by activation of inflammatory cytokines. Elevated circulating levels of HMGB1 also have been described in a case report of human hemorrhagic shock without evidence of infection [72
]. Serum HMGB1 levels are increased significantly within 24 h after the onset of hemorrhagic shock and return toward basal level as the clinical conditions improved.
Rheumatoid arthritis
In chronic inflammatory diseases such as arthritis, elevated HMGB1 levels have been reported in synovial fluid in experimental arthritis animal models as well as in human patients with rheumatoid arthritis [39
, 68
]. In comparison, patients with osteoarthritis had significantly less HMGB1 in the synovial fluid [39
]. In immunohistochemistry studies, tissues sections from synovitis patients showed the presence of cytoplasmic and extracellular HMGB1. This pattern of staining is significantly different from normal synovial tissue, which shows HMGB1 strictly localized in the nucleus [39
]. Administration of HMGB1 into mice joints also induced arthritis changes [62
] and stimulated the synovial macrophages to release proinflammatory cytokines including TNF, IL-1ß, and IL-6 [39
]. Considered together, these data indicate that HMGB1 plays a pathogenic role in arthritis.
These observations raise the possibility that HMGB1 may serve as a marker, as well as a mediator, of critical illness in the absence or presence of infection. Studies are in progress to elucidate whether elevated HMGB1 levels in sepsis patients are predictive of prognosis.
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ANTI-HMGB1 TREATMENT IN INFLAMMATORY DISEASES
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A growing body of evidence has indicated that HMGB1, released passively by necrotic or damaged cells or actively by macrophages/monocytes, causes inflammatory responses [7
, 35
, 43
, 44
]. Passive immunization with anti-HMGB1 antibodies significantly protects against lethal endotoxemia in mice, even when treatment was delayed 2 h after LPS exposure [7
, 8
]. The effects of anti-HMGB1 antibodies were dose-dependent and were effective even after the peak of circulating TNF was resolved [7
]. Similar protective effects were observed with other anti-HMGB1 treatment by A box, a DNA-binding motif of HMGB1 and a specific HMGB1 antagonist [8
], or ethyl pyruvate, a nontoxic food additive and an experimental anti-inflammatory agent [73
]. Besides endotoxemia, the protection conferred by anti-HMGB1 treatment also applies to other models of inflammation. Delayed treatment with anti-HMGB1 antibodies or other antagonists (A box or ethyl pyruvate) dose-dependently rescued mice from lethal sepsis induced by cecal perforation, and treatment was effective even when the first dose was given at 24 h after the cecal ligation and puncture surgery [8
, 73
]. Recently developed anti-HMGB1 monoclonal antibodies confirmed these findings [74
]. In vitro studies showed that A box competitively inhibits 125I-labeled HMGB1 cell-surface binding and attenuates HMGB1-induced proinflammatory cytokine release in macrophage-like RAW 264.7 cells [8
], and ethyl pyruvate specifically attenuates LPS-induced HMGB1 release and inhibits p38 MAPK and NF-B activation in macrophage cultures [73
]. Thus, anti-HMGB1 treatment, by HMGB1 antibodies, specific antagonist A box, or anti-inflammatory agent ethyl pyruvate, can rescue mice from lethal, systemic inflammation even with delayed treatment (2 h after LPS administration and 24 h after cecal ligation and puncture surgery). It is thus feasible to develop HMGB1-targeted, therapeutic strategies for the clinical management of lethal systemic inflammatory diseases (Fig. 5
).
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Figure 5. HMGB1 inhibitors as potential therapeutics in the treatment of sepsis. Bacterial toxins [i.e., LPS, toxic shock syndrome toxin 1 (TSST-1)] activate macrophages to release proinflammatory cytokines including HMGB1. Small amounts of cytokine are beneficial to the host by enhancing the innate-immune response to pathogens and leading to recovery from infection. Large amounts of proinflammatory cytokine (i.e., HMGB1) are toxic and could cause tissue injury, septic shock, and death. Anti-HMGB1 polyclonal or monoclonal antibodies, inhibitors (e.g., ethyl pyruvate) or antagonist (e.g., A box), protect against sepsis lethality, even when the first dose of treatment was given at 24 h after cecal perforation. Therefore, anti-HMGB1 treatment may have therapeutic potential in treatment of sepsis and gives a wider window for the treatment opportunity.
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Besides systemic inflammatory disease, anti-HMGB1 treatment, using HMGB1 antibodies or specific antagonist A box, has shown beneficial effects in collagen-induced arthritis in rodents [69
]. Therefore, an anti-HMGB1-based therapeutic strategy may also be useful in chronic inflammatory diseases such as arthritis.
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PERSPECTIVES
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The discovery of HMGB1 as a proinflammatory cytokine has initiated a new field of investigation for the development of therapeutics in the treatment of sepsis. This raises many important questions, such as the mechanisms of HMGB1 release from cells, cell-surface receptors, and downstream signal transduction pathways. Despite the difficulties with targeting cytokine activity in the treatment of sepsis, the pursuit of HMGB1 is clearly warranted by the nature of its delayed release, potency as a proinflammatory cytokine, and role as a mediator in inflammatory responses, including lung injury, intestinal barrier dysfunction, arthritis, endotoxemia, sepsis, and death. Hopefully, this anticytokine-based therapy will be evaluated soon in clinical trials of inflammatory diseases, where an excessive amount of HMGB1 is produced.
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ACKNOWLEDGEMENTS
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This work is partially supported by grants from The North Shore-Long Island Jewish Health System, General Clinical Research Center, M01 RR018535, and from National Institutes of Health, National Institute of General Medical Sciences (to K. J. T.).
Received November 8, 2004;
accepted February 3, 2005.
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ABSTRACT
INTRODUCTION