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Ó 2010 John Wiley & Sons A/S JOURNAL OF PERIODONTAL RESEARCH doi:10.1111/j.1600-0765.2010.01296.x
18b-Glycyrrhetinic acid inhibits periodontitis via glucocorticoid-independent nuclear factor-jB inactivation in interleukin10-deﬁcient mice
Sasaki H, Suzuki N, AlShwaimi E, Xu Y, Battaglino R, Morse L, Stashenko P. 18bGlycyrrhetinic acid inhibits periodontitis via glucocorticoid-independent nuclear factor-jB inactivation in interleukin-10-deﬁcient mice. J Periodont Res 2010; 45: 757–763. Ó 2010 John Wiley & Sons A/S Background and Objective: 18b-Glycyrrhetinic acid (GA) is a natural antiinﬂammatory compound derived from licorice root extract (Glycyrrhiza glabra). The eﬀect of GA on experimental periodontitis and its mechanism of action were determined in the present study. Material and Methods: Periodontitis was induced by oral infection with Porphyromonas gingivalis W83 in interleukin-10-deﬁcient mice. The eﬀect of GA, which was delivered by subcutaneous injections in either prophylactic or therapeutic regimens, on alveolar bone loss and gingival gene expressions was determined on day 42 after initial infection. The eﬀect of GA on lipopolysaccharide (LPS)-stimulated macrophages, T cell proliferation and osteoclastogenesis was also examined in vitro. Results: 18b-Glycyrrhetinic acid administered either prophylactically or therapeutically resulted in a dramatic reduction of infection-induced bone loss in interleukin-10-deﬁcient mice, which are highly disease susceptible. Although GA has been reported to exert its anti-inﬂammatory activity via downregulation of 11b-hydroxysteroid dehydrogenase-2 (HSD2), which converts active glucocorticoids to their inactive forms, GA did not reduce HSD2 gene expression in gingival tissue. Rather, in glucocorticoid-free conditions, GA potently inhibited LPSstimulated proinﬂammatory cytokine production and RANKL-stimulated osteoclastogenesis, both of which are dependent on nuclear factor-jB. Furthermore, GA suppressed LPS- and RANKL-stimulated phosphorylation of nuclear factorjB p105 in vitro. Conclusion: These ﬁndings indicate that GA inhibits periodontitis by inactivation of nuclear factor-jB in an interleukin-10- and glucocorticoid-independent fashion.
H. Sasaki1, N. Suzuki2, E. AlShwaimi3, Y. Xu4, R. Battaglino1, L. Morse5, P. Stashenko1
1 Department of Cytokine Biology, The Forsyth Institute, Boston, MA, USA, 2Pulp Biology and Endodontics, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan, 3 Restorative Dental Sciences Department, Endodontic Division, College of Dentistry, King Faisal University, Dammam, Saudi Arabia, 4 Department of Medical Microbiology and Immunology, Kunming Medical University, Yunnan, China and 5Department of Physical Medicine and Rehabilitation, Harvard Medical School and Spaulding Rehabilitation Hospital, Boston, MA, USA
Dr Hajime Sasaki, DDS, Ph.D, Department of Cytokine Biology, The Forsyth Institute, 140 The Fenway, Boston, MA 02115, USA Tel: +1 617 262 5200 Fax: +1 617 262 4021 e-mail: email@example.com Key words: 18b-glycyrrhetinic acid; periodontal disease; nuclear factor-jB; interleukin-10-deficient mouse Accepted for publication April 14, 2010
20.) injection on days 0.C. olive oil (highly reﬁned. The use of animals was approved by the Forsyth Institutional Animal Care and Use Committee. including modulation of glucocorticoid (GC) metabolism. were purchased from Sigma-Aldrich (St Louis. harvested. Control animals received injections of olive oil alone following the prophylactic schedule. and resuspended at 1010 cells/ ml in phosphate-buﬀered saline containing 2% carboxymethyl cellulose (CMC. Qiagen. The GAPDH gene was used as an internal control. which correlated with an inhibition of 11bhydroxysteroid dehydrogenase-2 (HSD2). USA). 2. ME. All reactions were carried out in triplicate.129P2-Il10tm1Cgn/J) on a C57BL/ 6J background were purchased from the Jackson Laboratory (Bar Harbor. 20. including Porphyromonas gingivalis (1). at 2 day intervals.758 Sasaki et al. USA) and TRIzol reagent (Invitrogen. In traditional medicine. CA. CA. gingivalis was determined by RT-PCR as described below. and soluble in dimethyl sulfoxide (DMSO)]. 10 mL/100 mL of drinking water] to reduce endogenous Gene expression of HSD1. gingivalis-induced periodontal disease. GA reduced inﬂammatory bone destruction. In addition. 27 and 34 relative to infection with P. For prophylaxis. HSD2. We have previously reported that IL-10deﬁcient mice are highly susceptible to P. and were disrupted by FastPrep-24 using Matrix A (both from MP Biomedicals. USA). Valencia. To test therapeutic eﬀects. gingivalis W83 was grown. However. MO. low acidity) and DMSO. Dimethyl sulfoxide alone served as a control. . GA was injected S. In the present study. Material and methods Reagents and treatments Reagents. despite these correlative data. including 18b-glycyrrhetinic acid [molecular weight 470. HSD1 (QT00107303). USA). beginning on day 0. gingivalis. 27 and 34 after infection. The level of gene expression was determined by comparison with standard curves generated with known copy number samples.70 g/mol. which converts active corticosteroids to their inactive forms (8). 11. Animals were then orally inoculated with 109 P. 5–7). The hypothesis tested was that GA inhibits periodontitis via local increases in active GCs that is mediated by a downregulation of HSD2. Sigma-Aldrich) as previously described (9). This ﬁnding suggests that increased local active GC is a possible mechanism of GA-mediated inhibition of inﬂammation. Bone loss measurements Alveolar bone loss was determined on digital images of mandibular molar teeth and alveolar bone morphometrically as previously described (9). b7-integrin (QT00105091) and RANKL (QT00147385) were used with the QuantiFast SYBR Green PCR Kit (Qiagen) following the manufacturerÕs instructions. IL-12 p40 and b7-integrin in gingival tissue was assessed by qPCR as previously described (10). including inﬂammation. Mice in GA-treated groups were given an olive oil suspension of GA (30 mg dose/kg body weight) following two treatment regimens. In experimental arthritis. OH. 13. Thus.to 7-week-old mice received antibiotic treatment [sulfatrim suspension (concentration of sulfamethoxazole/ trimethoprim oral suspension is 200/40 mg/5 mL). 10 mM GA in DMSO was diluted to 10 or 1 lM in culture medium. total RNA samples. To conﬁrm the colonization of P. insoluble in water and ethanol. Quantitative RT-PCR (qPCR) and RTPCR Interleukin-10-deﬁcient (IL-10)/)) mice (B6. 18b-Glycyrrhetinic acid (GA) is an active component of licorice root extract (Glycyrrhiza glabra). Bacterial culture and infection regimen P. Colonization of mice by P. but that this is likely to involve modulation of the proinﬂammatory transcription factor NF-jB rather than inhibition of HSD2 and local GC levels. USA). Sample preparation Animals were killed on day 42 after the initial oral infection. For in vitro studies. Prior to oral infection.3). we investigated possible therapeutic eﬀects of GA on infection-stimulated alveolar bone loss in a well-established IL-10-deﬁcient mouse model of periodontitis (9). Gingival tissues were isolated for RNA extraction. Animals were maintained under speciﬁc pathogen-free conditions in the Forsyth Institute animal facility as previously described (10). consistent with their hyperinﬂammatory response phenotype (10). hemisected and deﬂeshed for bone loss measurements as previously described (9). which contain both host and bacterial RNA. Predesigned primers for GAPDH (catalog number QT00309099. alteration of interleukin-10 (IL-10) production and downregulation of nuclear factor-jB (NF-jB. We here demonstrate that GA inhibits periodontal bone loss in this model. ulcers and cancer (4). GA was delivered by subcutaneous (S. 4. beneﬁcial therapeutic eﬀects of GA have been reported in various diseases. 13. regulation of the host immune and inﬂammatory response is a possible therapeutic strategy in ameliorating this disease. Mandibles were isolated. host immune responses play an important role in the induction and disease progression (2. Mice oral ﬂora (9). on days 9. the precise mechanism(s) of action of GA remains unclear. Negative control animals received the same volume of CMC without bacteria.C. 6. gingivalis six times. gingivalis 16S rRNA gene as described previously (10). Periodontitis is a chronic inﬂammatory bone destructive disease that is induced by a complex of oral pathogens. Carlsbad. purity 97%. were subjected to RT-PCR to detect the P. Solon. Several mechanisms of the GA-mediated anti-inﬂammatory eﬀect have been proposed. Results are expressed in millimeters squared. HSD2 (QT00252609). gingivalis W83.
18b-Glycyrrhetinic acid modestly upregulated T cell proliferation compared with positive controls. HyClone. Rocky Hill. Sigma-Aldrich. CA. coli LPS-stimulated IL-10)/) macrophages in vitro. GA profoundly inhibited the formation of TRAP-positive osteoclast-like polykaryons in a RAW264. 3A. Sigma-Aldrich. Strikingly. The IL-10)/) mice were infected orally with P. whereas there was no eﬀect on IL-6. USA).7 cells by recombinant mouse RANKL (PeproTech. USA). oral infection of IL-10)/) mice with with P. Resident peritoneal macrophages isolated from IL-10)/) mice (11) were plated at 105 cells per well in 96-well plates (n = 4). 3B). we determined the . phosphorylated NF-jB2 p100 and phosphorylated NF-jB p105 were detected using speciﬁc antibodies (Cell Signaling Technologies. After the incubation. NJ.13. USA) was used for all cell culture experiments. USA). USA) following the manufacturerÕs instructions. 18bGlycyrrhetinic acid also failed to inhibit IFNc production by T cells (Fig. because these genes are crucial in the induction of Th1 immune responses as well as for osteoclastogenesis (10. Austin. Effect of GA on gingival gene expression Interleukin-1b. As shown in Fig. Minneapolis. and instead upregulated HSD2 gene expression in the treated animals. no signiﬁcant eﬀect of GA on these genes was observed on day 42 (data not shown). IL-6. MA. but not in non-infected. Cytokine concentrations were expressed in picograms per milliliter. and interferon-c (IFNc) were quantiﬁed by ELISA (R&D Systems. coli lipopolysaccharide (LPS. After SDS-PAGE of protein samples (10 lg). San Jose. expression of HSD1 and HSD2 by qPCR on day 42. We also examined the eﬀect of GA on gingival gene expression of IL-12 p40. Infection was conﬁrmed by the detection of P. GA (30 mg/kg) administered either prophylactically (days 0–32) or therapeutically (days 9–34) completely inhibited P. USA). We therefore evaluated gingival gene To further explore the mechanism of GA action. WI. we examined the eﬀect of GA on T cell proliferation and IFNc production. and TRAP-positive polykaryons with more than three nuclei were enumerated as osteoclastlike cells (12). gingivalis-induced bone loss. indicating a lack of toxicity of this compound. 18b-Glycyrrhetinic acid did not modulate the expression of HSD1. gingivalis-induced alveolar bone loss Osteoclastogenesis was induced in RAW264. GA also failed to reduce HSD2 gene expression in gingival tissue (Fig. gingivalis induced signiﬁcant alveolar bone loss after 42 days compared with uninfected control animals. Essentially no TRAP-positive cells were observed in GA-treated cultures. MA. IL-12. animals on day 42 as determined by RT-PCR. Waltham. Next. USA) and stimulated with concanavalin A (Con A. gingivalis as described in the Material and methods section.07). The proliferation of T cells was determined using the CellTiter 96 Aqueous assay (Promega. and were stimulated with E. resulting in bone levels that were indistinguishable from uninfected control animals. b7-integrin and RANKL. 1. culture supernatants were subjected to ELISA for cytokines. As shown in Fig. The cells were also subjected to protein extraction for western blot. As shown in Fig. Adherent macrophages were subjected to protein extraction for western blot. we determined whether GA inhibits proinﬂammatory cytokine production by E. Surprisingly. However. we determined the eﬀect of GA on RANKL-stimulated osteoclastogenesis. 3C. which degrades glucocorticoids. Statistics The eﬀect of GA treatment was evaluated statistically by one-way ANOVA with the Bonferroni multiple comparison test. again indicating that it is not toxic. MN. secondary to an increase in the expression of IL-12 and the induction of strong T helper 1 (Th1) responses. GA signiﬁcantly suppressed the production of IL-1b and IL-12 p70 by macrophages in a dose-dependent fashion. Madison. gingivalis in all infected. 2).7 cell model. TX. Danvers. 1 lg/mL) in the presence or absence of GA for 7 days. Finally. Osteoclast differentiation Effect of GA on P. although this difference was not statistically signiﬁcant (p = 0. Mouse GAPDH served as a control (antibody from Ambion.14). ELISA We have previously characterized IL10-deﬁcient mice as a hyperinﬂammatory model of periodontitis. 2 lg/mL) for 24 h at 37°C in an atmosphere of 5% CO2– 95% air. NF-jB2 p100/ p52. Since macrophages and T cells play key roles in the induction of periodontitis in IL-10)/) mice (10). T cell proliferation assays Cellular protein was extracted using Tris–Glycine SDS Sample Buﬀer (Invitrogen).18b-Glycyrrhetinic acid inhibits periodontitis Macrophage cultures Protein extraction and western blot 759 Culture medium RPMI1640 (SigmaAldrich) supplemented with 2 mM L-glutamine (Invitrogen) and 10% charcoal–dextran-treated fetal bovine serum (to remove glucocorticoids. 18b-Glycyrrhetinic acid suppresses phosphorylation of NF-jB It has been suggested that GA acts by inhibiting the expression of HSD2. Suppressive effect of GA on cell functions in IL-10)/) mice Results Splenic T cells isolated from IL-10)/) mice (10) were plated at 105 cells per well in 96-well plates coated with antimCD3/mCD28 antibodies (both from BD Biosciences.
Open columns: infected. (A) Representative images of deﬂeshed hemimandibles.4 Exposed cementum (mm2) 1. 18b-Glycyrrhetinic acid does not inhibit gingival gene expression of HSD1 or HSD2. Change-fold value . (B) Eﬀect of GA on alveolar bone loss. 4A).2 1.1 1 0. In addition. no treatment). eﬀects of GA on the activation of NF-jB in vitro.0 0. GA inhibited RANKL-induced phosphorylation of NF-jB p105 (Fig.5 1. Shaded columns: negative control (no infection. The area enclosed by black line is the area of exposed cementum. Vertical bars represent SD. These data suggest that inhibition of NF-jB phosphorylation may underlie the protective anti-inﬂammatory eﬀect of GA on P. Negative: non-infected. Values are expressed as multiples of the positive control (change-fold values).8 0.0 3. n = 9. n = 9.9 0.0 N 11β-HSD1 11β-HSD2 Fig. Positive: P. Lipopolysaccaride-induced phosphorylation of NF-jB p105 in IL-10)/) macrophages was signiﬁcantly downregulated by 1 lM of GA (Fig.05 by ANOVA/Bonferroni test. gingivalis infected. 18b-Glycyrrhetinic acid inhibits the induction and progression of infection-induced alveolar bone loss in interleukin-10-deﬁcient mice. No signiﬁcant diﬀerences were detected by ANOVA/Bonferroni test. Therapeutic: P. GA 30 mg/kg. *p < 0. There was no eﬀect of GA on the phosphorylation of NF-jB2 p100/p52 or NF-jB2 p100 (data not shown).7 iv tiv ct at si la G Pr Aop hy G Th Aer ap eg Po eu tic e e ic * * * Fig. 1.3 1.0 1. Gingival gene expression of HSDs was determined by qPCR on day 42. Prophylactic: P. day 9– 34. vehicle alone.0 2. Vertical bars represent SD. n = 8. gingivalis infected. 4B). A B 1. Filled columns: positive control (infected. 2. no treatment). treated with prophylactic regimen. n = 8. gingivalis-induced periodontitis in IL-10)/) mice.760 Sasaki et al. day 0–34. vehicle alone. gingivalis infected. GA 30 mg/kg. 4.
(A) The eﬀect of GA on cytokine production by LPS-stimulated IL-10)/) macrophages. no GA. 3.18b-Glycyrrhetinic acid inhibits periodontitis A Macrophages IL-1β 400 300 200 100 0 * * * 400 300 200 100 0 * pg/mL IL-12p70 * 1000 800 600 400 200 0 * IL-6 761 μM μM μM μM N eg at iv tiv N eg at iv tiv N eg at iv 10 1 10 1 tiv μM 10 A G * Po si Po si Po si A A A G A G G B T cells Proliferation 1. no GA. gingivalis-induced bone loss when A B Fig.0005 by ANOVA/Bonferroni test. 18b-Glycyrrhetinic acid also has therapeutic Po si A A G A G A tiv e A 1 μM e e e e e e . Lane 3: GA (RANKL. no GA. *p < 0. Vertical bars represent SD. Discussion 18b-Glycyrrhetinic acid has been used as an anti-inﬂammatory agent for more than 2000 years (4). no GA. suggesting a mode of action of GA that is exerted at the time of. we chose IL-10)/) mice as a stringent model to test the therapeutic potential and mechanism of action of GA.7 cells. GA: RANKL. periodontal disease initiation.8 0.05 by ANOVA/Bonferroni test. Lane 2: positive (RANKL. *p < 0. (C) The eﬀect of GA on RANKL-stimulated osteoclastogenesis by RAW264. Negative: no ConA. G delivered in either prophylactic or therapeutic regimens. GA 10 or 1 lM. Lane 1: negative (vehicle alone). 18b-Glycyrrhetinic acid suppresses proinﬂammatory cytokine production and osteoclastogenesis in vitro. gingivalis induces ﬁve times more alveolar bone loss in IL10)/) than in wild-type C57BL/6J mice that are resistant to periodontitis (10).7 cells. As we previously reported. GA: Con A. IL-10)/) mice have a hyperinﬂammatory phenotype and are highly susceptible to P. 18b-Glycyrrhetinic acid inactivates the phosphorylation of NF-jB p105. n = 4 per group. Vertical bars represent SD.4 0 * * * pg/mL 2000 1600 1200 800 400 0 * IFNγ * G C Osteoclastogenesis Osteoclast 400 300 200 100 0 Polykaryons * * μM μM μM μM μM 10 A G G A G 1 μM e e e e N eg at iv tiv N eg at iv tiv e N eg at iv 10 1 Po si Po si 10 1 G Fig. as well as following. 4. vehicle). GA: LPS. and in recent studies inhibited joint destruction in experimental adjuvant-induced autoimmune arthritis (8). via inhibition of HSD2. 1 lM GA). vehicle). no GA. Lane 2: positive (LPS.05 by ANOVA/Bonferroni test. Positive: LPS. Lane 1: negative (vehicle alone). no GA. Hence. gingivalis-induced periodontitis is dependent on a hyperinﬂammatory state established via IL-12-mediated polarized Th1 immune responses (10). Positive: RANKL. The protective eﬀect of GA on arthritis has been attributed to local increases in GC levels. *p < 0. (B) Inactivation of NF-jB in RANKL-stimulated RAW264. GA 10 or 1 lM. which mediates GC inactivation. gingivalis-induced alveolar bone destruction (9). (B) The eﬀect of GA on T cell proliferation and IFNc production. Negative: no LPS. Negative: no RANKL.6 A490 1. the susceptibility of IL-10)/) mice to P. we demonstrate that GA completely inhibits P.2 0. In the present studies. (A) Inactivation of NF-jB in LPS-stimulated IL-10)/) macrophages. Positive: Con A. n = 4 per group. Oral infection of P. GA 10 or 1 lM. 1 lM GA). Vertical bars represent SD. n = 4 per group. Lane 3: GA (LPS.
In contrast. a model of microgravity in which animals rapidly become osteoporotic (23). which converts inactive GCs to their active form (5). Thus. The apparent lack of eﬀect of GA on GC metabolism in periodontitis compared with arthritis models may reﬂect inherent diﬀerences in the pathways activated by infection compared with an autoimmune disease. Although Rel-A [v-rel reticuloendotheliosis viral Acknowledgements We thank Mina Milosavljevic. these data strongly indicate that GA-mediated blockade of infection-stimulated alveolar bone loss is dependent on its ability to inhibit the activation of NF-jB and does not involve modulation of GCs or IL-10. we demonstrate that GA can exert its inhibitory eﬀects via an HSD. In contrast. Teng YT. J Dent Res 2006.and P. as noted earlier. In contrast. other mechanisms of action have been reported (6. and Mr Subbiah Yoganathan for animal husbandry. IFNc and T cell proliferation.S. may play an important role in infectionstimulated bone loss. Of interest. suggesting a GA-independent upregulatory pathway of active GCs. Glycyrrhizin enhances interleukin-10 production by liver dendritic cells in mice with hepatitis. 5.and GCindependent mechanism. These ﬁndings suggest that NF-jB1.762 Sasaki et al.113:248–252. Schuster D. in a sepsis arthritis model.) from the National Institute of Dental and Craniofacial Research/National Institutes of Health. 7. since it signiﬁcantly suppressed ligature. However. but not NF-jB2. such as proinﬂammatory cytokines (28). IL-6. The observation that GA inhibits bone loss in both IL-10)/) and wild-type animals clearly indicates that its mode of action is IL-10 independent. Kim JA. which is a sterile inﬂammatory condition. alpha) in the canonical pathway (24). In contrast. 4. Onji M.120:849–862. unpublished observations). for technical assistance with cell cultures and assays.38:962–967. indicating that the HSD–GC axis appears not to be a key mechanism in GA-mediated suppression of alveolar bone loss. 2.34). Nuclear factor-jB1 was also upregulated in bone marrow cells derived from tail-suspended mice.85:209–219. Classen-Houben D. impact in wild-type animals. Protective and destructive immunity in the periodontium: Part 1 – innate and humoral immunity and the periodontium. Kang OH. all of which are less NF-jB dependent (18–21). However.7). In contrast to autoimmune arthritis (8).S. 6. indicating the complexity of the GA–HSD2–GC axis.85:198– 208. unpublished observations). GA signiﬁcantly suppressed a number of NF-jB-dependent events. Abe M. References 1. we found that GA failed to downregulate gingival expression of HSDs.. further studies are essential to examine precisely the eﬀect of GA on the NF-jB pathways and HSD–GC axis using NF-jB1)/) and HSD2)/) mice (33. which is an infection-induced inﬂammation that also involves urethra and eyes (26). Rel-A was reported as a key molecule in inhibition of osteolytic osteomyelitis (25). Horiike N.17). but does not aﬀect HSD1. Consistent with NF-jB as a primary point of regulation (22). P. systemic inhibition of NF-jB2 using antisense oligonucleotides failed to suppress bone loss (27).) and DE09018 (to P. Haffajee AD. 18b-Glycyrrhetinic acid has been reported to mediate anti-inﬂammatory eﬀects in target tissues by increasing active GCs via downregulation of HSDs (15). 3. 11b-Hydroxysteroid dehydrogenase-2 was elevated in autoimmune arthritis (30) and was also signiﬁcantly upregulated in synovial macrophages of rheumatoid arthritis patients compared with normal synovium (31).S. 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Yakugaku Zasshi 2000. were unaﬀected. whereas NF-jB2 is involved in the non-canonical pathway. in GC-free conditions in vitro. Teng YT.15:981–985. This work was supported in part by grants DE-15888 (to H. 11b-Hydroxysteroid dehydrogenases are key regulators of GC pre-receptor metabolism (15). NF-jB2 appears to be important in induction of juvenile idiopathic arthritis and psoriatic arthritis (29). a scholar in the Forsyth Educational Outreach Program. non-canonical pathway activation closely relates to autoimmunity. GA completely inhibited RANKL-stimulated osteoclastogenesis and LPS-induced phosphorylation of NF-jB p105 (NF-jB1). Periodontol 2000 1994. Int J Mol Med 2005. Da Cunha T et al. Shibata S. and pharmacology of licorice. Inhibition of interleukin-8 production in the human colonic epithelial cell line HT-29 by 18 beta-glycyrrhetinic acid. but not NF-jB2 p100/p52 or NF-jB2 p100. J Gastroenterol 2003. . 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