A Dalbergia odorifera extract improves the survival of endotoxemia model mice by inhibiting HMGB1 release
© The Author(s). 2017
Received: 1 September 2016
Accepted: 5 April 2017
Published: 12 April 2017
Dalbergia odorifera T. Chen (Leguminosae) is an indigenous medicinal herb that is widely used as a popular remedy in northern and eastern Asia. However, the cellular mechanisms underlying the biological activity of D. odorifera are not fully elucidated.
Anti-inflammatory effect of D. odorifera extract (DOE) was determined through intraperitoneal injection in a mouse model of endotoxemia induced by lipopolysaccharide (LPS). RAW 264.7 cells, a murine macrophage, were also treated with LPS to generate a cellular model of inflammation, and investigated the anti-inflammatory activity and underlying mechanisms of DOE and its constituent isoliquiritigenin.
DOE dose-dependently inhibited LPS-induced release of high mobility group box 1 (HMGB1), a late proinflammatory cytokine, and decreased cytosolic translocation of HMGB1 in RAW264.7 cells. This inhibitory effect of DOE on HMGB1 release was observed in cells treated with DOE before or after LPS treatment, suggesting that DOE is effective for both treatment and prevention. In addition, DOE significantly inhibited LPS-induced formation of nitric oxide (NO) and expression of inducible NO synthase (iNOS) in a dose-dependent manner. These effects of DOE were accompanied by suppression of HMGB1 release triggered by LPS, suggesting a possible mechanism by which DOE modulates HMGB1 release through NO signaling.
Isoriquiritigenin, a constituent of DOE, also attenuated LPS-triggered NO formation and HMGB1 release in RAW264.7 cells, indicating that isoriquiritigenin is an indexing molecule for the anti-inflammatory properties of DOE. Furthermore, c-Jun N-terminal kinase, but not extracellular signal-regulated kinase and p38, mediated DOE-dependent inhibition of HMGB1 release and NO/iNOS induction in RAW 264.7 cells exposed to LPS. Notably, administration of DOE ameliorated survival rates in a mouse model of endotoxemia induced by LPS, where decreased level of circulating HMGB1 was observed.
These results suggest that DOE confers resistance to LPS-triggered inflammation through NO-mediated inhibitory effects on HMGB1 release.
KeywordsDalbergia Odorifera Endotoxemia HMGB1 Inflammation Nitric oxide
High mobility group box 1 (HMGB1) is a evolutionarily conserved non-histone nuclear protein that is ubiquitously expressed in most eukaryotic cells . In the nucleus, HMGB1 interacts with histones to regulate key processes including replication, transcription, recombination, genome stabilization, and repair . In addition to its nuclear localization, HMGB1 is secreted into the extracellular compartment by immunocompetent cells activated upon exposure to pathogen-associated molecular patterns such as lipopolysaccharide (LPS), in which it acts as a proinflammatory cytokine . The proinflammatory activity of HMGB1 was first demonstrated in a sepsis mouse model as a late mediator of lethality, in which HMGB1 is actively secreted by activated macrophages . In addition, serum levels of HMGB1 were elevated with delayed kinetics in sepsis patients showing overwhelmed cellular inflammatory and immune responses, resulting in multiple organ failure, tissue damage, and death [4–6]. Recent studies indicated the roles of extracellular HMGB1 in inflammation-associated disease pathogenesis; the administration of neutralizing anti-HMGB1 antibodies or HMGB1 inhibitors significantly reduces inflammatory conditions in sepsis, arthritis, colitis, and ischemic reperfusion [4, 7–9]. Notably, blockade of HMGB1 signals by these reagents confers cellular protection from delayed endotoxin lethality in a mouse model of endotoxemia, even when applied after the acute phase of cytokine responses has peaked, indicating that HMGB1 is a novel target for inflammatory diseases [4, 10, 11]. As part of the endeavor to target HMGB1 release, we demonstrated that rosiglitazone, an activator of the nuclear protein peroxisome proliferator-activated receptor (PPAR) γ, inhibits LPS-triggered release of HMGB1 in RAW264.7 cells . Furthermore, PPARγ-mediated upregulation of SIRT1 expression participates in the inhibitory action of PPARγ through deacetylation-mediated interaction of SIRT1 and HMGB1, leading to improvement of the survival of endotoxemia model mice [13, 14]. Based on the proinflammatory properties of HMGB1, the blockade of its release into the extracellular milieu is a promising molecular target for the diseases associated with inflammatory disorders.
Herbal extracts and components from Prunella vugaris, Danggi, and mung bean have recently been demonstrated to effectively inhibit HMGB1 release induced by LPS [15–17]. Several molecular mechanisms by which herbal components effectively block HMGB1 release are postulated . Glycyrrhizin inhibits LPS-triggered HMGB1 release through binding to HMGB1 in order to induce conformational changes that prevent DNA binding [18, 19]. Furthermore, epigallocatechin-3-gallate and tanshinone IIA stimulate autophagic degradation and endocytic uptake of HMGB1 in RAW264.7 cells, respectively [20, 21]. On the other hand, Dalbergia odorifera, a folk medicinal herb, exhibits a beneficial effect in inflammatory conditions via the induction of heme oxygenase (HO)-1, an anti-inflammatory protein, in murine RAW 264.7 macrophages and BV2 microglial cells [22, 23]. These anti-inflammatory activities of D. odorifera stem from a number of compounds such as flavonoids, phenolic constituents, and quinines isolated from its heartwood [24, 25]. Given the ability of several herbal components to inhibit LPS-triggered cellular responses for inflammation, we investigated the effect of a 60% ethanol extract of D. odorifera on HMGB1 release in LPS-treated RAW264.7 cells and a mouse model of endotoxemia. Here, we report that a D. odorifera extract (DOE) inhibited LPS-triggered release of HMGB1 in macrophages and an animal model of endotoxemia. DOE suppressed LPS-induced nitric oxide (NO) signaling by preventing the c-Jun N-terminal kinase (JNK) signaling cascade, leading to blockade of HMGB1 release into the extracellular milieu.
LPS (Escherichia coli 0111:B4), Ponceau S solution, N G-monomethyl-L-arginine (L-NMMA), daidzein, formononetin, isoliquilirigenin, and a rabbit polyclonal antibody specific for β-actin were obtained from Sigma-Aldrich Co. (St. Louis. MO, USA). Dalbergin were purchased from R&D chemicals (Bethesda, MD, USA) and the sativanone standard was generously provided by Dr. Hiroshi Noguchi (School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan). Piperidinewas purchased from JUNSEI (Tokyo, Japan). SP600125 [Anthra (1,9-cd)pyrazol-6(2H)-one] was obtained from Calbiochem (La Jolla, CA, USA). Monoclonal antibodies specific for inducible NO synthase (iNOS) and HMGB1 were supplied by Epitomics (Burlingame, CA, USA). Rabbit polyclonal antibodies specific for p38, phospho-p38, extracellular signal-regulated kinase (ERK), phospho-ERK, JNK, and phospho-JNK were purchased from Cell Signaling (Beverly, MA, USA). Monoclonal antibodies specific for lamin B and α-tubulin were purchased from Santa Cruz Biotechnology (Dallas, TX, USA).
Preparation of DOE
DOE was prepared according to a previously described method . Briefly, heartwood of D. odorifera was purchased from a Korean medicinal herb store in Seoul in May 2012. An authenticated voucher specimen (KULBM-1205) was deposited in the Herbarium at the College of Animal Bioscience and Technology, Konkuk University (Seoul, Korea). Dried heartwood of D. odorifera (100 g) was extracted three times with 60% ethanol under rotation of 120 rpm for 1 h. After evaporation of the solvent under a vacuum, the extract (10 g) was reconstituted in dimethyl sulfoxide to a concentration of 10 mg/ml and then stored at −20 °C until use.
LC-MS/MS parameters for quantitation and confirmation
Declustering potential DP(V)
Entrance potential EP(V)
Collision energy CE(V)
Collision cell exit potential CXP(V)
Murine RAW 264.7 macrophages were incubated in DMEM containing 10% heat-inactivated fetal calf serum and 1% antibiotics at 37 °C under a condition of 5% CO2 and 95% air.
Western blot analysis
Aliquots of total cell lysates were subjected to immunoblot analysis as essentially described . In brief, whole-cell lysates containing 30 μg protein per lane were fractionated on a 10% SDS-polyacrylamide gel electrophoresis (PAGE) and blotted onto a polyvinylidene difluoride (PVDF) membrane (Amersham Biosciences UK Ltd., UK; Hybond-P+, 0.45 μm pore). Following blocking with 5% nonfat milk, the membranes were probed with specific antibodies. Finally, after reaction with a peroxidase-conjugated goat antibody, immuno-reactive proteins were visualized by West-ZOL Plus (iNtRON Biotechnology).
Determination of secreted HMGB1
HMGB1 secretion was determined according to an essentially described method . Briefly, the relative amounts of HMGB1 secreted into culture media were determined from conditioned culture media of equal numbers of cells. Equal volumes of conditioned culture media and 80% cold acetone were mixed and incubated at −20 °C for 1 h. Following centrifugation at 16,000×g for 10 min at 4 °C, the precipitates were washed with 80% cold acetone. The resulting pellets resuspended in SDS-PAGE sample buffer were subjected to Western blot analysis. As a loading control, Ponceau S staining was used.
Measurement of NO
NO formation was measured spectrophotometrically as its stable oxidative metabolite, nitrite, formed by reactions with Griess reagents as described previously . Briefly, 100 μl of culture medium was mixed with the same volume of Griess reagents [one part of 1% sulfanilamide in 0.1 M HCl and one part of 0.1% N-(1-naphthyl)ethylenediamine dihydrochloride]. Following reaction for 10 min, optical density was determined at 550 nm in a microplate reader (Bio-Rad, Hercules, CA, USA). The nitrite concentration was determined with a curve calibrated using sodium nitrite standards. The background levels of nitrite in the culture media were subtracted from each sample.
Fractionation of cytoplasmic and nuclear proteins
Cytosolic and nuclear fractions were prepared according to a previously described method . Briefly, RAW264.7 cells washed with ice-cold PBS were suspended in lysis buffer (0.1 mM EDTA, 1 mM DTT, 10 mM KCl, 10 mM HEPES, and protease inhibitors, pH 7.9) and allowed to swell on ice for 15 min. After adding Nonidet P-40 (0.1%, final concentration), cell lysates were vortexed vigorously for 10 s. The cytosolic fraction, a supernatant, was obtained by centrifugation at 13,000×g for 30 s. The resulting pellet was washed with lysis buffer and resuspended in PRO-PREP Protein Extraction Solution (iNtRON Biotechnology). Following incubation for 30 min on ice, the supernatant, as the nuclear fraction, was collected by centrifugation at 13,000×g at 4 °C for 15 min. Bradford method was used to determine protein concentration.
Animal model of endotoxemia and survival test
The Institutional Animal Care and Use Committee of Konkuk University approved all animal studies of the present study (approval number: KU15140). Endotoxemia was induced by infusion of bacterial endotoxin by intraperitoneal injection (10 mg/kg, E. coli LPS 0111:B4) into BALB/c mice (male, 6-week-old, 20–25 g) as described previously . Briefly, BALB/c mice purchased from Koatech (Pyeongtaek, Korea) were housed in a pathogen-free environment. Mice were randomly assigned to the following groups: injection of LPS (10 mg/kg), simultaneous injection of LPS (10 mg/kg) plus DOE (20 mg/kg), and DOE (20 mg/kg) administration after LPS (10 mg/kg) infusion. Follow LPS injection, survival rate was assessed for up to 2 weeks to confirm the additional late deaths. To measure plasma HMGB1 levels, sepsis was induced in mice by LPS injection in the absence or presence of DOE as described above. After 20 h, blood was collected and allowed to clot at room temperature. Following centrifugation at 1600×g for 20 min, the HMGB1 levels in serum were detected by immunoblot.
One-way ANOVA followed by the Tukey-Kramer test was used to determine the statistical significance.
DOE inhibits LPS-triggered release of HMGB1 in RAW 264.7 cells
Because HMGB1 translocates from the nucleus to the cytoplasm upon the activation of macrophages by inflammatory signals such as LPS , we examined whether DOE affects the translocation of HMGB1 to the cytoplasm induced by LPS. When RAW 264.7 cells were triggered by LPS, the re-localization of HMGB1 from the nucleus into the cytoplasm was increased, whereas this cytosolic translocation of HMGB1 was markedly inhibited in the presence of DOE (Fig. 2b). This indicates that DOE regulates HMGB1 release by inhibiting re-localization of HMGB1 into the cytoplasm in RAW 264.7 cells exposed to LPS.
DOE attenuates LPS-triggered release of HMGB1 in RAW 264.7 cells even when administered after LPS treatment
DOE inhibits LPS-induced NO formation in RAW 264.7 cells
DOE inhibits LPS-triggered release of HMGB1 through NO in RAW 264.7 cells
To verify the involvement of NO signaling in the LPS-triggered release of HMGB1 in RAW 264.7 cells, we next examined the effects of L-NMMA on the LPS-triggered release of HMGB1 in the presence or absence of DOE. In LPS-treated RAW 264.7 cells, addition of L-NMMA inhibited HMGB1 release to a similar extent as DOE (Fig. 5b). However, the results obtained upon treatment with both DOE and L-NMMA were not different from those obtained upon treatment with either alone, indicating that the inhibitory activity of DOE is mediated through the NO signaling pathway (Fig. 5b).
Identification of DOE constituents
Anti-inflammatory effect of isoliquiritigenin
DOE inhibits LPS-triggered activation of JNK to suppress HMGB1 release in RAW 264.7 cells
To further investigate whether the JNK signaling pathway is involved in LPS-induced HMGB1 release, we examined the effect of a specific inhibitor of JNK on RAW 264.7 cells exposed to LPS. The LPS-induced increase in HMGB1 release was almost completely abolished in the presence of SP600125, an inhibitor of JNK, and the extent of inhibition was similar to that achieved with DOE (Fig. 8c). However, the results obtained upon combined treatment with both DOE and SP600125 were not different from those obtained upon treatment with either alone, indicating that the action of DOE in the inhibition of HMGB1 release is mediated via the JNK signaling pathway. In addition, SP600125 and DOE inhibited NO formation and iNOS expression to a similar extent in LPS-exposed RAW 264.7 cells and there was no additive effect upon combined treatment, suggesting that JNK mediates DOE-mediated inhibition of HMGB1 release via the NO signaling cascade (Fig. 8d).
DOE attenuates LPS-triggered lethality by inhibiting HMGB1 release
Despite recent advances in therapeutics, sepsis remains one of the most lethal incurable diseases. As part of our ongoing efforts to identify natural products with anti-inflammatory activity, we report here that an ethanol extract of D. odorifera and its constituent isoliquiritigenin inhibited LPS-triggered release of HMGB1 by blocking NO signaling, which was mediated via suppression of JNK. Furthermore, administration of DOE significantly improved the survival rates in a mouse model of endotoxemia, with a concomitant reduction in the level of circulating HMGB1.
To our knowledge, this is first report demonstrating that DOE inhibits HMGB1 release in murine RAW264.7 macrophages exposed to LPS. The anti-inflammatory effect of DOE may be due to its effects on cellular signaling cascades, as demonstrated in this study. In fact, the neoflavonoid latifolin isolated from a methanol extract of D. odorifera attenuates inflammatory responses by inactivating nuclear factor (NF)-κB through nuclear transcription factor-E2-related factor 2 (Nrf-2)-mediated upregulation of HO-1 . In line with the present finding, isoliquiritigenin, another constituent of D. odorifera, is a powerful anti-inflammatory molecule that protects against the effects of LPS by inhibiting interleukin-1β, tumor necrosis factor-α, and NO production in RAW 264.7 cells . The anti-inflammatory activity of 4,2′,5′-trihydroxy-4′-methoxychalcone and butein, other components of D. odorifera, was also demonstrated in LPS-treated murine macrophages via upregulation of HO-1, which is involved in the resolution of inflammatory conditions [31, 32]. These findings are in line with our present results demonstrating significant DOE-mediated inhibition of HMGB1 release in RAW 264.7 cells stimulated by LPS. DOE and its active components may therefore also exert its action on the cellular response against inflammation by regulating LPS-induced release of HMGB1, which is a late-phase proinflammatory cytokine that plays an important role in the pathogenesis of sepsis .
Although three MAPKs are activated by LPS, they were not equally affected by DOE in murine macrophages. In the present study, DOE markedly reduced the effect of LPS on phosphorylation of JNK, but not ERK or p38. Consistent with this observation, the LPS-induced elevation of HMGB1 release was almost completely abolished by SP600125, an inhibitor of JNK. This finding is consistent with a previously reported study in which HMGB1 release was significantly inhibited by intravenous administration of SP600125 in the heart tissue of ischemia-reperfusion model rats . In normal human bronchial epithelial cells, SP600125 also inhibited HMGB1-mediated inflammatory responses through the inhibition of JNK signaling . In contrast with these reports, a recent study demonstrated that another MAPK, p38, is implicated in ketamine-mediated inhibition of HMGB1 release induced by LPS through upregulation of HO-1 . In addition, p38-dependent inhibition of HMGB1 release was also demonstrated in cellular or animal models of severe acute pancreatitis and endotoxemia upon administration of the natural products glycyrrhizin, Dachengqi decoction, and the tetrahydroisoquinoline alkaloid THI-28 [36–38]. Although the MAPK that is involved in the inhibition of HMGB1 release is controversial, the present data clearly demonstrated that JNK participates in DOE-mediated inhibition of HMGB1 release induced by LPS. Accordingly, the identity of the MAPK signaling pathway that is involved in the inhibition of HMGB1 release triggered by inflammatory stimuli may differ according to the nature of the individual compound used.
Among the regulatory mechanisms implicated in HMGB1 secretion, DOE and its constituent isoriquiritigenin inhibit LPS-triggered release of HMGB1 through the NO signaling cascade. The free radical gas NO, a small molecule mediator of inflammation, specifically inhibits HMGB1 release induced by LPS . Post-translational modifications such as acetylation and phosphorylation are the main regulatory mechanism underlying HMGB1 translocation in the cellular responses against bacterial endotoxin or proinflammatory cytokines [39, 40]. Consistent with these findings, our previous study showed that rosiglitazone and GW501516, which are specific activators of PPARγ and δ, respectively, inhibit the LPS-induced release of HMGB1 through an acetylation-dependent manner . Although the functional significance of the inhibition of HMGB1 release has been documented for diverse herbal extracts and components [18–21], the signaling cascades associated with the inhibition of HMGB1 release are now being elucidated. Accordingly, mechanistic studies, including the present data, on the signaling pathway involved in HMGB1 release and the post-translational modifications of HMGB1 itself are important to elucidate the anti-inflammatory actions of DOE via the inhibition of HMGB1 release.
In line with our findings in cultured murine macrophages, administration of DOE significantly attenuated endotoxin-induced lethality in vivo. Upon exposure to the bacterial endotoxin LPS, the level of circulating HMGB1 was reduced in mice treated with DOE, which was accompanied by an improvement in their survival rate, indicating that the effects of DOE on septic shock are HMGB1-dependent. Furthermore, administration of DOE, either together with LPS or after LPS treatment, inhibited LPS-triggered release of HMGB1, suggesting that DOE-mediated regulation of HMGB1 release is effective for both prevention and treatment. The present observation is consistent with previous reports in which blockade of HMGB1 attenuated endotoxin lethality in a mouse model of endotoxemia, even when administered after LPS injection [4, 10, 11]. DOE has also been known to regulate inflammatory reactions by inhibiting nuclear transcription factors, such as NF-κB and Nrf-2, thereby modulating expression of pro- or anti-inflammatory genes [22, 23]. However, little is known about the role of DOE in the regulation of HMGB1 release. Accordingly, the present observations indicate that DOE has anti-inflammatory constituents, which may play a pivotal role in pathological conditions. When seen in this light, inhibition of HMGB1 release in immune cells, which is possibly augmented in inflammatory conditions, may resolve the immune responses in the pathology of endotoxemia. Consequently, inhibitors of HMGB1 release, such as DOE, hold promise as therapeutic interventions in septic shock.
The present investigation indicates that ethanol extract of D. odorifera and its constituent isoliquiritigenin possess the promising anti-inflammatory activities in in vitro and/or in vivo models (Fig. 9c). When seen in this light, inhibition of HMGB1 release in immune cells, which is possibly augmented in inflammatory conditions, may resolve the immune responses in the pathology of endotoxemia. Consequently, inhibitors of HMGB1 release, such as DOE and possibly isoliquiritigenin, hold promise as therapeutic interventions in septic shock.
D. odorifera extract
Extracellular signal-regulated kinase
High mobility group box 1
Heme oxygenase 1
Inducible NO synthase
c-Jun N-terminal kinase
Mitogen-activated protein kinase
Nuclear transcription factor-E2-related factor 2
Peroxisome proliferator-activated receptor
This paper was supported by Konkuk University in 2015.
Availability of data and materials
The data supporting our findings are included within this manuscript.
HSC and HGS participated in research design. HSC, JAP, JSH, SAH, TY, and WJL carried out experiments. HSC, KSP, HCS, CHL, and HGS analyzed the data. HSC, KSP, and HGS wrote the manuscript. All authors read and approved the final manuscript.
HSC, Master’s course student in Konkuk University; JAP, JSH, and SAH, Post-doctoral researchers in Konkuk university; TY and WJL, Doctoral course students in Konkuk University; KSP, Professor in Semyung University; HCS, CHL, and HGS: Professors in Konkuk University.
The authors declare that they have no competing interest.
Consent for publication
All of authors have read this manuscript and approved for publication.
Ethic approval and consent to participate
This study was approved by the Institutional Animal Care and Use Committee of Konkuk University (approval number: KU15140).
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