Prostaglandin E2 Regulates Interleukin-1β-induced Matrix                Metalloproteinase-3 Production in Human Gingival Fibroblasts

Prostaglandin E2 (PGE2) exerts its biological actions via EP receptors (EP1, EP2, EP3, and EP4). In the present study, we investigated whether PGE2 regulated interleukin (IL)-1β-induced matrix metalloproteinase (MMP)-3 production in human gingival fibroblasts (HGF) derived from periodontally healthy subjects and diseased patients. In HGF from healthy gingiva, PGE2 down-regulated IL-1β-induced MMP-3 production, whereas in HGF from periodontitis patients, PGE2 enhanced it. Butaprost (an EP2 agonist) and ONO-AE1-329 (an EP4 agonist) suppressed IL-1β-induced MMP-3 production, and 17-phenyl-ω-trinor PGE2 (an EP1 agonist) mimicked the PGE2 effect in HGF from healthy and periodontally diseased tissues, respectively. Analysis of these data suggests that, in HGF from healthy tissue, IL-1β-induced MMP-3 production is down-regulated by PGE2 via EP2 and EP4 receptors, whereas in cells from periodontally diseased tissue, IL-1β-induced MMP-3 production is up-regulated via EP1 receptors. Different regulation of IL-1β-induced MMP-3 production by PGE2 between healthy and periodontally diseased tissues may be involved in the pathogenesis of periodontal disease.

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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

ISRN Pharmacology ◽

10.1155/2014/784019 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

Hiroyuki Kitamura ◽

Hiroko Urano ◽

Toshiaki Ara

Keyword(s):

Periodontal Disease ◽

Inflammatory Responses ◽

Human Gingival Fibroblasts ◽

Kampo Medicine ◽

Prostaglandin E ◽

Gingival Fibroblasts ◽

Extracellular Signal Regulated Kinase ◽

Erk Phosphorylation ◽

Extracellular Signal ◽

Cox 2

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 E2 (PGE2) 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 E2 (PGE2), IL-6, and IL-8 by human gingival fibroblasts (HGFs) treated with lipopolysaccharide (LPS) from Porphyromonas gingivalis. Kakkonto concentration dependently suppressed LPS-induced PGE2 production but did not alter basal PGE2 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 A2 (cPLA2), 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 cPLA2 phosphorylation. These results suggest that kakkonto decreased PGE2 production by inhibition of ERK phosphorylation which leads to inhibition of cPLA2 phosphorylation and its activation. Therefore, kakkonto may be useful to improve gingival inflammation in periodontal disease.

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