Effect of phenytoin on interleukin-1 beta production in human gingival fibroblasts challenged to tumor necrosis factor alpha in vitro

Effects and interaction of tumor necrosis factor alpha (TNF alpha) and the antiepileptic drug phenytoin (PHT) on interleukin-1 beta (IL-1 beta) production as well as on prostaglandin E(2) (PGE(2)) formation were studied in gingival fibroblasts in vitro. TNF alpha, in contrast to PHT, dose-dependently stimulated the production of cell-associated IL-1 beta. The stimulatory effect of TNF alpha on IL-1 beta production was accompanied by enhanced PGE(2) formation. When PHT and TNF alpha were added simultaneously, the drug potentiated the stimulatory effect of TNF alpha on both IL-1 beta production and PGE(2) formation. The major PHT metabolite, p-HPPH, did not affect IL-1 beta production, either alone or in combination with TNF alpha. The production of IL-1 beta induced by TNF alpha and the combination of TNF alpha and PHT was further enhanced in the presence of the prostaglandin endoperoxide (PGH) synthase inhibitors, indomethacin and flurbiprofen. The PHT-mediated enhancement of TNF alpha-induced IL-1 beta production and PGE(2) formation in gingival fibroblasts may be an important link in the pathogenesis of gingival overgrowth induced by PHT.