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

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Abstract
Keratinocytes immortalized by human papillomaviruses (HPV) 16 and 18 are partially resistant to the inhibition of proliferation exerted by transforming growth factor-β (TGF-β). To determine if this finding reflects a generalized resistance to inhibitory cytokines, we studied the effect of tumor necrosis factor-α (TNF-α) on subconfluent cultures of both normal and HPV-immortalized human foreskin keratinocytes. Whereas primary and HPV-16-immortalized keratinocytes were sensitive to TNF-α, 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-β to inhibit c-myc RNA expression in normal cells. Evidently, the resistance of HPV-immortalized keratinocytes to TNF-β and TGF-β proceeds along different regulatory pathways.