18β-glycyrrhetinic acid inhibits periodontitis via glucocorticoid-independent nuclear factor-κB inactivation in interleukin-10-deficient mice.
OBJECTIVE
18β-Glycyrrhetinic acid (GA) is a natural anti-inflammatory 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.


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
18β-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 11β-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 LPS-stimulated proinflammatory cytokine production and RANKL-stimulated osteoclastogenesis, both of which are dependent on nuclear factor-κB. Furthermore, GA suppressed LPS- and RANKL-stimulated phosphorylation of nuclear factor-κB p105 in vitro.


CONCLUSIONS
These findings indicate that GA inhibits periodontitis by inactivation of nuclear factor-κB in an interleukin-10- and glucocorticoid-independent fashion.
Sasaki
H
H
Department of Cytokine Biology, The Forsyth Institute, Boston, MA, USA Pulp Biology and Endodontics, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
Suzuki
N
N
Alshwaimi
E
E
Xu
Y
Y
Battaglino
R
R
Morse
L
L
Stashenko
P
P
D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000235:genetics; D016301:Alveolar Bone Loss / Q000188:drug therapy* / Q000382:microbiology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids; D006034:Glycyrrhetinic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D016753:Interleukin-10 / Q000172:deficiency*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010010:Osteoclasts / Q000187:drug effects; D010518:Periodontitis / Q000188:drug therapy* / Q000382:microbiology; D010766:Phosphorylation / Q000187:drug effects; D016966:Porphyromonas gingivalis; D013047:Specific Pathogen-Free Organisms; D013601:T-Lymphocytes / Q000187:drug effects
D005938:Glucocorticoids; D016328:NF-kappa B; D016753:Interleukin-10; C119129:18alpha-glycyrrhetinic acid; D042842:11-beta-Hydroxysteroid Dehydrogenases; D006034:Glycyrrhetinic Acid