title: Differential effect of tumor necrosis factor on proliferation of primary human keratinocytes and cell lines containing human papillomavirus types 16 and 18.
abstract: 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.
authors.affiliation: Ludwig Institute for Cancer Research, São Paulo, Brazil.
authors.forename: L L
authors.initials: LL
authors.lastname: Villa
authors.forename: K B
authors.initials: KB
authors.lastname: Vieira
authors.forename: X F
authors.initials: XF
authors.lastname: Pei
authors.forename: R
authors.initials: R
authors.lastname: Schlegel
mesh_terms: D015152:Blotting, Northern; D015153:Blotting, Western; D002455:Cell Division; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D006801:Humans; D015603:Keratinocytes / Q000166:cytology*; D010212:Papilloma / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D027383:Papillomaviridae / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D012367:RNA, Viral / Q000096:biosynthesis; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D012367:RNA, Viral; D014409:Tumor Necrosis Factor-alpha