The cytokines tumor necrosis factor-alpha (TNF-alpha) and TNF-related apoptosis-inducing ligand differentially modulate proliferation and apoptotic pathways in human keratinocytes expressing the human papillomavirus-16 E7 oncoprotein

Keratinocytes are the natural target cells for infection by human papilloma viruses (HPVs), most of which cause benign epithelial hyperplasias (warts), However, a subset of papillomaviruses, the "high risk" HPVs, cause lesions that can progress to carcinomas. Inflammatory mediators such as tumor necr osis factor-alpha (TNF-alpha) and TNF-related apoptosis-inducing ligand (TR AIL) are produced by cells in response to a viral infection. To determine t he effects of TNF-alpha and TRAIL on keratinocytes expressing the high risk HPV-16 oncoprotein E7, human foreskin keratinocytes stably expressing E7 w ere treated with TNF-alpha and TRAIL. Treatment with TNF-alpha alone, but n ot TRAIL, induced growth arrest and differentiation in keratinocytes that w as almost completely overcome by expression of HPV-16 E7. Both cytokines in duced apoptosis when administered in combination with the protein synthesis inhibitor cycloheximide, but the apoptotic response to TRAIL was significa ntly more rapid and efficient compared with the response seen after TNF-alp ha treatment. HPV-16 E7-expressing keratinocytes were more prone to both TN F-alpha- and TRAIL-mediated apoptosis compared with vector-infected control s.