Effect of phenytoin on collagen accumulation by human gingival fibroblasts exposed to TNF-αin vitro

T. Kato, N. Okahashi, T. Ohno, H. Inaba, S. Kawai, A. Amano

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)


OBJECTIVE: Tumor necrosis factor (TNF)-α is associated with chronic gingival inflammation and reported to induce gingival overgrowth (GO), while phenytoin (PHT) is also known to be a causative agent of GO. We examined the synergistic effect of PHT and TNF-α on collagen metabolism in human gingival fibroblasts (HGFs). MATERIALS AND METHODS: HGFs were cultured with TNF-α and PHT. Quantitative real-time RT-PCR was employed to determine the mRNA levels for collagen, matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) and integrin subunits. Cellular collagen endocytosis was determined using a flow-cytometry. RESULTS: The proliferation of HGFs was not affected by TNF-α or PHT individually, whereas both synergistically increased collagen accumulation in HGFs. Further, collagen mRNA expression was not increased by TNF-α or PHT, although together they markedly prevented cellular collagen endocytosis, associated with the suppression of α2β1-integrin mRNA expression. The mRNA expression of MMP-1 and-2 was suppressed by PHT, while TIMP-1 mRNA expression was enhanced by both TNF-α and PHT. CONCLUSION: Our results suggest that TNF-α and PHT together cause impaired collagen metabolism by suppression of enzymatic degradation with MMPs/TIMP-1 and integrin-mediated endocytosis. These synergistic effects may also be involved in TNF-α- and PHT-induced collagen accumulation, leading to GO.

Original languageEnglish
Pages (from-to)156-162
Number of pages7
JournalOral Diseases
Issue number2
Publication statusPublished - Mar 1 2006
Externally publishedYes


  • Antiepileptic drug
  • Collagen
  • Gingival fibroblasts
  • Gingival overgrowth
  • Phenytoin
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Otorhinolaryngology
  • Dentistry(all)


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