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Laboratories of
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Experimental Immunology and
Biomedical Science, North Shore-LIJ Research Institute;
Departments of Medicine and
Surgery, North Shore University Hospital;
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Department of Medicine, New York University School of Medicine; and
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Department of Surgery, Albert Einstein College of Medicine, Manhasset, NY 11030
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-8, TNF-, and RANTES. B box up-regulated CD83 expression as well as IL-6 secretion via a p38 MAPK-dependent pathway. In the MLR, B box-activated DCs acted as potent stimulators of allogeneic T cells, and the magnitude of the response was equivalent to DCs activated by exposure to LPS, nonmethylated CpG oligonucleotides, or CD40L. Furthermore, B box induced secretion of IL-12 from DCs as well as IL-2 and IFN-
secretion from allogeneic T cells, suggesting a Th1 bias. HMGB1 released by necrotic cells may be a signal of tissue or cellular injury that, when sensed by DCs, induces and/or enhances an immune reaction. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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High mobility group box protein 1 (HMGB1), a nuclear and cytosolic protein, was originally identified as an intranuclear factor with an important structural function in chromatin organization (9). Recently, HMGB1 was identified as a proinflammatory cytokine that mediates endotoxin lethality, local inflammation, and macrophage activation (10, 11, 12). HMGB1 administered in vivo induces arthritis when injected into murine joints (13) and acute lung injury when administered intra-articularly (14). HMGB1 is released by activated macrophages and monocytes after exposure to LPS, TNF-, or IL-1
and as a result of tissue damage (15, 16). It is a also a potent stimulating signal to monocytes and induces the delayed synthesis of proinflammatory cytokines (11). HMGB1 contains two homologous DNA-binding motifs, termed HMG A and HMG B boxes (17, 18). The proinflammatory domain of HMGB1 maps to the B box, which alone is sufficient to recapitulate the cytokine-stimulating effect of full-length HMGB1 in vivo (19). The intracellular abundance of HMGB1 and its proinflammatory activities suggest that its release at sites of cell injury or damage plays a role in the initiation and/or perpetuation of an immune response. Furthermore, as HMGB1 is found in the serum of patients with acute (sepsis) and chronic (rheumatoid arthritis) inflammatory conditions (10, 20), it may be involved in maladaptive or autoimmune responses.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human recombinant HMGB1 or recombinant B box (rB box) was expressed in Escherichia coli and purified to homogeneity as previously described (21). Briefly, B box (233 bp) was cloned by PCR amplification from a human brain Quick-Clone cDNA (Clontech Laboratories, Palo Alto, CA). The primers were 5'-AAGTTCAAGGATCCCAATGCAAAG-3' and 5'-GCGGCCGCTCAATATGCAGCTATATCCTTTTC-3'. The PCR product was subcloned into pCRII-TOPO vector EcoRI sites using the TA cloning method according to the manufacturer’s instructions (Invitrogen, Carlsbad, CA). After amplification, the PCR product was digested with EcoRI and subcloned into an expression vector (pGEX) with a GST tag (Amersham Pharmacia Biotech, Piscataway, NJ). The recombinant plasmid was transformed into protease-deficient E. coli strain BL21 (Novagen, Madison, WI) and incubated in 2-YT medium containing ampicillin (50 µg/ml) for 5–7 h at 30°C with vigorous shaking until an OD at A600 of 1–1.5 was achieved. Subsequently, fusion protein expression was induced by addition of 1 mM isopropyl--D-thiogalactoside for 3 h at 25°C. Bacteria were sonicated in ice-cold PBS plus 1x protease inhibitor mixture (Sigma-Aldrich, St. Louis, MO) and 1 mM PMSF. After centrifugation (8000 x g) to remove bacterial debris, the rB box was purified to homogeneity by glutathione-Sepharose resin column chromatography (Amersham Pharmacia Biotech). For use as a control in cell stimulation experiments, GST vector protein was expressed and purified similarly, then used as the control for experiments using GST-rB box protein. Protein elute was dialyzed extensively against PBS to remove the excess amount of reduced glutathione and was passed over a column with immobilized polymyxin B (Pierce, Rockford, IL) to remove LPS. The rB box purified to homogeneity contained trace amounts of LPS (19 pg LPS/µg rB box) as measured by the chromogenic Limulus amebocyte lysate assay (BioWhittaker, Walkersville, MD). For all stimulation experiments using the rB box, polymyxin B was added to the cell culture medium at 200 U/ml, an amount that completely neutralizes the activity of these amounts of LPS.
Inhibitors
The p38 MAPK-specific inhibitor, SB203580, a pyridinyl imidazole compound, the MEK inhibitor PD98059, and N-tosyl-L-phenylalanine chloromethyl ketone (TPCK) were purchased from Sigma-Aldrich. Because these required solubilization in DMSO, DMSO was used as a negative control.
Generation of receptor for advanced glycation end products (RAGE) antibodies
Polyclonal anti-RAGE Ab reactive with an extracellular region of human RAGE (peptide sequence SVKEQTRRHPETGLFTC) was raised in rabbits (Cocalica Biologicals, Reamstown, PA). IgG was purified using protein A-agarose (Pierce).
Trypsin treatment of HMGB1 B box
To proteolytically digest HMGB1 proteins, trypsin-EDTA was added to HMGB1 B box (0.05% final concentration), and digestion was conducted in 1x PBS (pH 7.4) at 25°C overnight. Degradation of proteins was verified by SDS-PAGE before and after trypsin digestion by Coomassie Blue staining.
T cell isolation
T cells were isolated by negative selection using the RosetteSep Ab mixture from StemCell Technologies (Vancouver, Canada) according to the manufacturer’s instructions. The cell purity of the isolated T cells was routinely 
99% pure.
Generation of DCs
PBMCs were isolated from the blood of normal volunteers (Long Island Blood Services, Melville, NY) over a Ficoll-Hypaque (Pharmacia Biotech, Uppsala, Sweden) density gradient. CD14+ monocytes were isolated from PBMCs by positive selection using anti-CD14 beads (Miltenyi Biotech, Auburn, CA) following the manufacturer’s instructions. To generate DCs, CD14+ cells were cultured in RPMI 1640 medium supplemented with 2 mM L-glutamine (Life Technologies, Grand Island, NY), 50 µM 2-ME (Sigma-Aldrich), 10 mM HEPES (Life Technologies), penicillin (100 U/ml)-streptomycin (100 µg/ml; Life Technologies), and 5% human AB serum (Gemini Bio-Products, Woodland, CA). Cultures were maintained for 7 days in six-well trays (3 x 106 cells/well) supplemented with 1000 U of GM-CSF/ml (Immunex, Seattle, WA) and 200 U of IL-4/ml (R&D Systems, Minneapolis, MN) on days 0, 2, 4, and 6.
Stimulation of DCs
On day 7 of culture, immature DCs were either left untreated (immature) or were stimulated with indicated doses of 1) LPS (E. coli serotype 026:B6, Sigma-Aldrich), 2) 500 ng/ml trimeric CD40L (Alexis Biochemicals, San Diego, CA), 3) a mixture of cytokines (CyC) consisting of IL-6 at 1000 U/ml, TNF- at 10 ng/ml, IL-1 at 10 ng/ml (all from R&D Systems), and PGE2 at 1 µg/ml (Sigma-Aldrich), or with 4) nonmethylated CpG oligonucleotides (5'-tcgtcgttttgtcgttttgtcgtt-3') at 30 µg/ml. The sequence of this oligonucleotide is known to induce DC maturation (4), except that it contains an unmodified phosphodiester backbone. In all experiments DCs were analyzed 48 h after stimulation. All experiments using the rB box were performed in the presence of polymyxin B sufficient to neutralize >10-fold more LPS than that present in rB box preparations.
Analysis of DC phenotype
DCs (1 x 104) were reacted for at least 20 min at 4°C in 100 µl of PBS/5% FCS/0.1% sodium azide (staining buffer) with PE-conjugated IgG specific for CD206, CD54, HLA-DR (all from BD Immunocytometry Systems, San Jose, CA), and CD83 (Immunotech-Beckman Coulter, Marseilles, France) or with FITC-conjugated IgG mAb specific for CD80, CD40, and CD58 (all from BD Immunocytometry Systems). Cells were then washed four times with staining buffer, fixed in 10% formaldehyde in PBS (pH 7.2–7.4), and examined by flow cytometry using a FACScan (BD Biosciences, Mountain View, CA). In all experiments isotype controls were included using an appropriate PE- or FITC-conjugated irrelevant mAb of the same Ig class.
Measurement of cytokines and chemokines
Forty-eight hours after activation, the production of cytokines and chemokines in cell culture supernatants was measured by ELISA (Pierce Boston Technology Center, SearchLight Proteome Arrays Multiplex Sample Testing Services, Woburn, MA).
MLR
To assess levels of cellular activation and proliferation, cells were plated at 105 cells/well in a round-bottom, 96-well tray at DC:T cell ratios of 1:120 for 5 days in the medium described above. The microcultures were pulsed with [3H]thymidine (1 mCi/well) for the final 8 h of culture. Cell cultures were harvested onto glass-fiber filters with an automated multiple sample harvester, and the amount of isotope incorporation was determined by liquid scintillation beta emission. Responses are reported as the mean cpm of thymidine incorporation by triplicate cultures ± SEM.
EMSA
DCs were collected 48 h after activation and were washed once in PBS. Nuclear extract was isolated using NE-PER nuclear and cytoplasmic extraction reagents according to the manufacturer’s instructions (Pierce). For detection of NF-
B binding, nuclear extract from cells (5 µg of protein) was incubated with 0.2 ng of 32P-labeled double-stranded oligonucleotide sequence in a 10-µl reaction volume containing 5x gel shift binding buffer (20% glycerol, 5 mM MgCl2, 2.5 mM EDTA, 2.5 mM DTT, 250 mM NaCl, 50 mM Tris-HCl (pH 7.5), and 0.25 mg/ml poly(dI-dC)-poly(dI-dC)) for 30 min at room temperature. For supershift experiments, 1 µl of Ab against the indicated NF-B family members (Santa Cruz Biotechnology, Santa Cruz, CA) was added to the reaction mix 5 min before loading onto the gel. The samples were resolved on a 4% polyacrylamide gel and visualized directly by autoradiography after drying the gel. The NF-B consensus sequence (E3292; Promega, Madison, WI) was labeled with 10 U of T4 polynucleotide kinase (M4101; Promega)/25 ng oligo, 1x kinase buffer, and 5 µl of [-32P]ATP (PB10168, Amersham Pharmacia Biotech; 10 mCi/ml) for 30 min at 37°C. Unbound ATP was determined on a Sephadex G-25 column (Amersham Pharmacia Biotech, Piscataway, NJ).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine whether HMGB1 can induce DC maturation, recombinant HMGB1 was added to immature DCs, and increases in CD83, MHC class II, CD54, CD86, and CD40 expression and a decrease in CD206 expression were observed (Fig. 1A). Previous work has linked the proinflammatory domain of HMGB1 to the B box (21). Immature DCs were exposed to rB box or other known maturation stimuli: LPS, CyC, nonmethylated CpG oligonucleotides, and CD40L (see Materials and Methods). The rB box increased the cell surface density of CD83, CD54, CD58 CD40, and MHC class II and decreased the density of the macrophage mannose receptor, CD206. The B box-induced changes were quantitatively similar to those produced by the other stimuli (Fig. 1B).
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In addition to changes in surface molecule expression, the secretion of inflammatory cytokines and chemokines characterizes DC maturation. The rB box, when cultured with immature DCs, induced the secretion of IL-12 (p70), TNF-, IL-6, IL-1, RANTES, and IL-8 (Fig. 2A). IL-10 levels were either not detected or were very low (<10 pg/ml). IL-2, IFN-, and TGF- did not increase beyond detectable levels (data not shown). The GST control (see Materials and Methods; vector) did not induce the secretion of these factors (Fig. 2A). Furthermore, the rB box induced the secretion of IL-8 and TNF- at levels similar to those produced by the other stimuli (Fig. 2B).
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B box induces functional maturation of DCs and leads to a Th1-polarized immune response
Mature, cytokine-producing DCs induce T cell activation and proliferation, leading to the development of adaptive immunity (1, 2). In coculture experiments, DCs matured by exposure to B box, activated resting allogeneic T cells. The magnitude of this stimulation was equivalent to DCs that had been matured by exposure to LPS, CyC, nonmethylated CpG oligonucleotides, or CD40L (Fig. 4A), indicating that the rB box induced functional maturation of DCs. DCs matured with rB box or the other stimuli were cultured with allogeneic T cells for 5 days, and subsequently the culture supernatants were analyzed for the presence of Th1 and Th2 cytokines. IFN- levels were the highest in the rB box-matured DC-T cell cocultures (Fig. 4B). All stimuli up-regulated IL-2 7-fold over immature DCs. IL-2 levels in rB box-stimulated DC cultures (51.1 ± 22.4 pg/ml) were similar to those produced by the other stimuli (42.4 ± 8.4 pg/ml). IL-5 was up-regulated by each of the stimuli, albeit to differing levels: CyC-stimulated DCs 42-fold over immature DCs (277.4 ± 242.6 pg/ml), rB box activated DCs 26-fold (143.7 ± 142.4 pg/ml), and the other stimuli activated DCs 12-fold (147.2 ± 30 pg/ml). IL-4 was not detected after exposure to any of the stimulants.
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B
HMGB1 is a ligand for RAGE, a membrane protein that transduces intracellular signaling, thereby leading to nuclear translocation of NFB (22, 23). Using immunofluorescence techniques, RAGE was detected on the cell surface of immature DCs (Fig. 5A). As signaling through NF-B also plays a role in DC maturation (24, 25, 26), we tested whether B box activated NF-B using an EMSA. As expected, immature DCs showed no active NF-B (27), whereas B box-stimulated DCs expressed levels of active NF-B comparable to those produced by CyC and LPS (Fig. 5B). To identify the NF-B subunits involved in B box-induced intracellular signaling, nuclear extracts from B box-activated DCs were analyzed by supershift assay. Anti-p65 Ab caused a significant supershift in protein/DNA complex motility, indicating that the p65 subunit is a component of the complex activated by the B box (Fig. 5C). Abs against p52 and Rel B did not cause supershifts (data not shown). Unlabeled NF-B-specific DNA probes displaced the NF-B-DNA complex, indicating specificity for the NF-B consensus sequence (Fig. 5C).
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To obtain insight into the roles of ERK and p38 MAPK pathways in B box-induced DC maturation, we used their specific inhibitors, PD98059 and SB203580, respectively. To analyze the role of NF-B, we used TPCK, a serine protease inhibitor that blocks nuclear translocation of Rel/NF-B by preventing IB degradation. The p38 MAPK inhibitor SB203580, but not the other inhibitors, completely abrogated B box-induced up-regulation of CD83 and down-regulated B box-induced secretion of IL-6 (Fig. 6).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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by T cells, the rB box functions as a Th1-polarizing stimulus. The receptor involved in HMGB1-mediated DC activation is not yet fully defined, although HMGB1 is a specific ligand for RAGE (22). Signaling through RAGE can activate a cascade involving NF-B (23). We have detected RAGE expression on the surface of immature DCs and found that B box induces activation of the p65 (RelA) subunit of NF-B. This is in agreement with results seen in B box-activated RAW 264.7 cells (21) and HMGB1-activated murine neutrophils (28). The role of this subunit in immunological functions is still unknown. However, a recent report showed that RelA is necessary for the expression of genes in mouse embryonic fibroblasts that are involved in the activation of immune responses (29). These results raise the possibility that HMGB1 signals DC maturation through RAGE. Interestingly, even though NF-B activation plays a role in the maturation of human DCs (24, 25, 26), its inhibition using TPCK did not change B box-induced expression of CD83 or alter secreted levels of IL-6. This suggests that B box induces those changes by a NF-B-independent and p38-dependent mechanism. Another possible receptor for HMGB1 is the TLR2, as there is some evidence that activation of NFB by necrotic cells depends on TLR2 (30). While the present paper was under review, it was shown that HMGB1 may signal through TLR2 and TLR4 (28) in murine neutrophils isolated from the LPS-resistant mouse strain C3H/HeJ. These results are in contrast to those reported by Yang et al.3 showing that HMGB1, rB box, and B box peptide signal through TLR2, but not TLR4. As in the present study of DC maturation (Fig. 3, D and E), the 17-mer synthetic peptide was sufficient to signal through TLR2. MAPK activation also contributes to the maturation of human DCs (31, 32, 33). Using the p38 MAPK inhibitor SB203580, we found that rB box-induced up-regulation of cell surface CD83 and secretion of IL-6 by DCs was dependent on the p38 MAPK pathway. In addition, as ERK has been implicated in cell survival of a murine DC cell line (26), we inhibited the ERK pathway using the specific MEK1/2 inhibitor PD98059; this inhibition altered neither B box-induced CD83 expression nor IL-6 secretion.
Collectively these data demonstrate that HMGB1 and its B box can function as maturation stimuli for human monocyte-derived immature DCs and, as such, represent endogenous immunostimulatory molecules. Endogenous DC-stimulating factors are intriguing because they may represent a class of well-tolerated natural adjuvants (5).
In contrast, such molecules may facilitate the breaking of tolerance and thereby promote or potentiate autoimmunity. Elevated levels of HMGB1 have been detected in the synovial fluid of patients with rheumatoid arthritis (20), and HMGB1 injected into the joints of mice induces arthritic changes (13). The amount of HMGB1in synovial fluid is similar to the amount of HMGB1 that we found sufficient to induce DC maturation in vitro. Local microenvironments in other autoimmune diseases such as systemic lupus erythematosus or multiple sclerosis may also have high HMGB1 levels, providing a milieu in which DCs could be activated by self-Ags.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: DC, dendritic cell; CyC, cytokine mixture; HMGB1, high mobility group box protein 1; RAGE, receptor for advanced glycation end products; rB box, recombinant B box; TLR, Toll-like receptor; TPCK, N-tosyl-L-phenylalanine chloromethyl ketone.
3 M. Yu, H. Wang, J. Li, L. Yang, R. Obar, W. Newman, J. M. Mason, D. T. Golenbock, E. Latz, C. J. Czura, M. J. Fenton, U. Andersson, K. J. Tracey, and H. Yang. HMGB1 signals through Toll-like receptor 2. Submitted for publication.
Received for publication September 26, 2003. Accepted for publication April 27, 2004.
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B pathway. Int. Immunol. 12:1539.B require the cytoplasmic domain of the receptor but different downstream signaling pathways. J. Biol. Chem. 274:19919.B and octamer factors is a hallmark of the generation and maturation of dendritic cells. Blood 95:277.B in regulation of multiple immune-response genes and in Fas-induced cell death. J. Exp. Med. 189:999.B/Toll-like receptor pathway in induction of inflammatory and tissue-repair gene expression by necrotic cells. J. Immunol. 166:7128.-induced activation and maturation of human peripheral blood monocyte-derived dendritic cells. J. Immunol. 162:3865., and contact sensitizers. J. Immunol. 166:3837.This article has been cited by other articles:
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