Caffeic acid phenethyl ester (CAPE) has numerous potentially beneficial properties, including anti-oxidant, immunomodulatory and anti-inflammatory activities. However, the effect of CAPE on periodontal disease has not been studied before. This study was designed to investigate the efficacy of CAPE in ameliorating the production of proinflammatory mediators in macrophages activated by LPS from Prevotella intermedia, a pathogen implicated in periodontal disease. CAPE exerted significant inhibitory effects on P. intermedia LPS-induced production of NO, IL-1β and IL-6 as well as their mRNA expression in RAW264.7 cells. CAPE induced HO-1 expression in cells activated with P. intermedia LPS, and selective inhibition of HO-1 activity by tin protoporphyrin IX significantly attenuated the inhibitory effect of CAPE on LPS-induced NO production. CAPE did not interfere with IκB-α degradation induced by P. intermedia LPS. Instead, CAPE decreased nuclear translocation and DNA binding activity of NF-κB p50 subunit induced with LPS. In addition, CAPE showed strong inhibitory effects on LPS-induced STAT1 and STAT3 phosphorylation. Further, CAPE significantly elevated the expression of SOCS1 mRNA in P. intermedia LPS-stimulated cells. Overall, this study suggests that CAPE inhibits P. intermedia LPS-induced production of NO, IL-1β and IL-6 in murine macrophages through anti-inflammatory HO-1 induction and inhibition of NF-κB, STAT1 and STAT3 activation, which is possibly related to the activation of SOCS1 signaling. Modulation of host response by CAPE may represent an attractive strategy towards the treatment of periodontal disease. In vivo studies are underway to further appraise the potential of CAPE as an immunomodulator in the treatment of periodontal disease.

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2013R1A1A2007625).