Differential effect of tumor necrosis factor on proliferation of primary human keratinocytes and cell lines containing human papillomavirus types 16 and 18

Mol Carcinog. 1992;6(1):5-9. doi: 10.1002/mc.2940060103.


Keratinocytes immortalized by human papillomaviruses (HPV) 16 and 18 are partially resistant to the inhibition of proliferation exerted by transforming growth factor-beta (TGF-beta). To determine if this finding reflects a generalized resistance to inhibitory cytokines, we studied the effect of tumor necrosis factor-alpha (TNF-alpha) on subconfluent cultures of both normal and HPV-immortalized human foreskin keratinocytes. Whereas primary and HPV-16-immortalized keratinocytes were sensitive to TNF-alpha, HPV-18-immortalized keratinocytes (and those immortalized by simian virus 40) were resistant to the inhibitory effects of this cytokine. The ability of HPV-18 to induce a more resistant phenotype correlated with its more potent in vitro transforming activity and its apparent association with more aggressive tumors. Interestingly, the state of TNF-induced growth inhibition in normal or HPV-16-immortalized keratinocytes was not accompanied by a reduction in the expression of c-myc RNA or protein. This contrasts sharply with the ability of TGF-beta to inhibit c-myc RNA expression in normal cells. Evidently, the resistance of HPV-immortalized keratinocytes to TNF-alpha and TGF-beta proceeds along different regulatory pathways.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Blotting, Northern
  • Blotting, Western
  • Cell Division
  • Cell Line
  • Cell Transformation, Neoplastic
  • Cells, Cultured
  • Humans
  • Keratinocytes / cytology*
  • Papilloma / metabolism
  • Papilloma / microbiology
  • Papilloma / pathology*
  • Papillomaviridae / genetics*
  • Papillomaviridae / metabolism
  • Proto-Oncogene Proteins c-myc / biosynthesis
  • RNA, Viral / biosynthesis
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Proto-Oncogene Proteins c-myc
  • RNA, Viral
  • Tumor Necrosis Factor-alpha