Periodontitis is a chronic inflammatory disease that results in gingival inflammation and periodontal tissue destruction and is accompanied by alveolar bone resorption and eventual tooth loss. We examined the effect of 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) on periodontitis by inhibiting the production of interleukin-6 (IL-6).Osteoblast-like cells MC3T3E-1 were pretreated with 15d-PGJ 2 before being incubated with lipopolysaccharide (LPS), the effect of 15d-PGJ 2 on IL-6 production, expression and its regulatory mechanisms were studied by reverse transcription-polymerase chain reaction (RT-PCR), Western blot, electrophoretic mobility shift assay (EMSA), and confocal laser scanning microscopy study.15d-PGJ 2 inhibits LPS-stimulated IL-6 production in a concentration-dependent manner in osteoblast-like cells MC3T3E-1, without appreciable cytotoxicity. To further examine the mechanism responsible for the inhibition of IL-6 production by 15d-PGJ 2 , we examined the effect of 15d-PGJ 2 on nuclear factor-κB (NF-κB) activation and the phosphorylation of protein kinase B (Akt). 15d-PGJ 2 treatment clearly reduced the DNA binding activity of NF-κB in LPS-stimulated osteoblast-like cells MC3T3E-1, an effect that was mediated by inhibiting the degradation of inhibitor κB (IκB) and nuclear translocation of NF-κB p65 subunit. In addition, 15d-PGJ 2 attenuated the LPS-mediated Akt pathway. These effects of 15d-PGJ 2 were not abrogated by the PPARγ antagonist, GW9662, indicating that they are PPARγ-independent actions.These results suggest that 15d-PGJ 2 possess a potent suppressive effect on inflammatory responses of osteoblast-like cells MC3T3E-1 via the Akt and NF-κB pathways independent of PPARγ and suggest that this compound may offer some insight into the development of a new therapeutic approach to the prevention and treatment of periodontal diseases.