Preventive Effects of a Kampo Medicine, Kakkonto, on Inflammatory Responses via the Suppression of Extracellular Signal-Regulated Kinase Phosphorylation in Lipopolysaccharide-Treated Human Gingival Fibroblasts

Periodontal disease is accompanied by inflammation of the gingiva and destruction of periodontal tissues, leading to alveolar bone loss in severe clinical cases. The chemical mediator prostaglandin E(2) (PGE(2)) and cytokines such as interleukin- (IL-)6 and IL-8 have been known to play important roles in inflammatory responses and tissue degradation. In the present study, we investigated the effects of a kampo medicine, kakkonto (TJ-1), on the production of prostaglandin E(2) (PGE(2)), IL-6, and IL-8 by human gingival fibroblasts (HGFs) treated with lipopolysaccharide (LPS) from Porphyromonas gingivalis. Kakkonto concentration dependently suppressed LPS-induced PGE(2) production but did not alter basal PGE(2) levels. In contrast, kakkonto significantly increased LPS-induced IL-6 and IL-8 production. Kakkonto decreased cyclooxygenase- (COX-)1 activity to approximately 70% at 1 mg/mL but did not affect COX-2 activity. Kakkonto did not affect cytoplasmic phospholipase A(2) (cPLA(2)), annexin1, or LPS-induced COX-2 expression. Kakkonto suppressed LPS-induced extracellular signal-regulated kinase (ERK) phosphorylation, which is known to lead to ERK activation and cPLA(2) phosphorylation. These results suggest that kakkonto decreased PGE(2) production by inhibition of ERK phosphorylation which leads to inhibition of cPLA(2) phosphorylation and its activation. Therefore, kakkonto may be useful to improve gingival inflammation in periodontal disease.