18beta-Glycyrrhetinic Acid Inhibits Periodontitis Via Glucocorticoid-Independent NF–κB Inactivation In IL-10 Deficient Mice Hajime Sasaki a,* , Noriyuki Suzuki b , Emad AlShwaimi c , Yan Xu d , Ricardo Battaglino a , Leslie Morse e , and Philip Stashenko a a Department of Cytokine Biology, The Forsyth Institute, 140 The Fenway, Boston, MA 02115, U.S.A b Pulp Biology and Endodontics, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan c Restorative Dental Sciences Department, Endodontic Division, College of Dentistry, King Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia d Department of Medical Microbiology and Immunology, Kunming Medical University, Yunnan, China 650031 e Department of Physical Medicine and Rehabilitation, Harvard Medical School and Spaulding Rehabilitation Hospital, 125 Nashua Street, Boston, MA 02114 USA Abstract Background and objective—18beta-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 IL-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 LPS-stimulated macrophages, T cell proliferation, and osteoclastogenesis was also examined in vitro. Results—GA administered either prophylactically or therapeutically dramatically reduced infection-induced bone loss in IL-10 deficient mice, which are highly disease-susceptible. Although GA has been reported to exert its anti-inflammatory activity via down-regulation of 11- beta hydroxysteroid dehydrogenase-2 (HSD2), which converts active glucocorticoids (GC) to their inactive forms, GA did not reduce HSD2 gene expression in gingival tissue. Rather, under GC- free conditions, GA potently inhibited LPS-stimulated proinflammatory cytokine production and RANKL-stimulated osteoclastogenesis, both of which are NF–κB-dependent. GA furthermore suppressed LPS- and RANKL-stimulated phosphorylation of NF–κB p105 in vitro. Conclusion—These findings indicate that GA inhibits periodontitis by inactivation of NF–κB in an IL-10 and GC-independent fashion. * Corresponding Author: Dr. Hajime Sasaki, Department of Cytokine Biology, The Forsyth Institute, 140 The Fenway, Boston, MA 02115, U.S.A., hsasaki@forsyth.org, TEL: +1-617-892-8459, FAX: +1-617-262-4021. NIH Public Access Author Manuscript J Periodontal Res. Author manuscript; available in PMC 2011 April 13. Published in final edited form as: J Periodontal Res. 2010 December ; 45(6): 757–763. doi:10.1111/j.1600-0765.2010.01296.x. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript