INFLAMMATORY MEDIATORS PRODUCED BY HUMAN GINGIVAL FIBROBLASTS (HGF) have been implicated in the initiation and progression of periodontal disease. The purpose of this study was to examine whether prostaglandin E(2) (PGE(2)), which is produced in abundance from HGF after stimulation with interleukin (IL)-1 beta or tumor necrosis factor-alpha (TNF-alpha), could regulate IL-6 production by HGF. HGF stimulated with either IL-1 beta or TNF-alpha showed a rapid and dose-dependent increase in IL-6 mRNA accumulation and IL-6 secretion, as demonstrated by reverse transcription-polymerase chain reaction analysis and bioassay. IL-6 secretion from either IL-1 beta- or TNF-alpha-stimulated HGF was enhanced by the inhibition of PGE(2) synthesis with indomethacin. Furthermore, the addition of PGE(2) inhibited IL-6 secretion from these cells. In contrast, indomethacin or PGE(2) did not affect the accumulation of IL-6 mRNA in IL-1 beta-stimulated HGF. These data indicate that IL-6 production by HGF is up-regulated by specific cytokines, IL-1 beta and TNF-alpha, and suggest that this production may be partially down-regulated by endogenous and exogenous PGE(2) at the post-transcriptional level.