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 papillomaviruses (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 necrosis factor-alpha (TNF-alpha) and TNF-related apoptosis-inducing ligand (TRAIL) are produced by cells in response to a viral infection. To determine the effects of TNF-alpha and TRAIL on keratinocytes expressing the high risk HPV-16 oncoprotein E7, human foreskin keratinocytes stably expressing E7 were treated with TNF-alpha and TRAIL. Treatment with TNF-alpha alone, but not TRAIL, induced growth arrest and differentiation in keratinocytes that was almost completely overcome by expression of HPV-16 E7. Both cytokines induced apoptosis when administered in combination with the protein synthesis inhibitor cycloheximide, but the apoptotic response to TRAIL was significantly more rapid and efficient compared with the response seen after TNF-alpha treatment. HPV-16 E7-expressing keratinocytes were more prone to both TNF-alpha- and TRAIL-mediated apoptosis compared with vector-infected controls.
Basile
J R
JR
Department of Oral Medicine and Diagnostic Sciences, Harvard School of Dental Medicine, Boston, Massachusetts 02115, USA.
Zacny
V
V
Münger
K
K
D051017:Apoptosis Regulatory Proteins; D002455:Cell Division / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000502:physiology*; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16