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 E2 (PGE2) 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 PGE2 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 PGE2 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 PGE2 formation in gingival fibroblasts may be an important link in the pathogenesis of gingival overgrowth induced by PHT.
Brunius
G
G
Department of Orthodontics and Pediatric Dentistry, Faculty of Odontology, Karolinska Institutet, Huddinge, Sweden.
Yucel-Lindberg
T
T
Shinoda
K
K
Modéer
T
T
D002648:Child; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005480:Flurbiprofen / Q000494:pharmacology; D005881:Gingiva / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005885:Gingival Hyperplasia / Q000139:chemically induced / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis*; D010672:Phenytoin / Q000031:analogs & derivatives / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; C001419:hydroxyphenytoin; D005480:Flurbiprofen; D010672:Phenytoin; D015232:Dinoprostone; D007213:Indomethacin