Differential production of cytokines and activation of NF-kappaB in HPV-transformed keratinocytes.
We have proposed that chronic infection of keratinocytes by HPV modifies the expression of potentially important cytokines by interfering with the NF-kappaB signal pathway. We evaluated the constitutive and IL-1beta-induced expression of GM-CSF and TNF-alpha and the expression/activity of NF-kappaB in HPV+ and HPV- cell lines. Despite the enhanced expression of the functional components of the NF-kappaB signaling pathway in HPV+ cell lines by a mechanism implicating the HPV oncoprotein E6, the constitutive activity of NF-kappaB and the expression of GM-CSF/TNF-alpha were significantly reduced relative to the HPV- cell line and normal keratinocytes. In contrast, we observed a superactivation of NF-kappaB activity after IL-1beta stimulation, a strong and transient induction of GM-CSF/TNF-alpha mRNA, but undetectable levels of secreted proteins in HPV+ cell lines. Our data demonstrate that E6 modulates the NF-kappaB signaling pathway and suggest that other HPV proteins also interfere with GM-CSF/TNF-alpha expression by transcriptional and/or posttranscriptional mechanisms.
Havard
L
L
Department of Pathology, University Hospital of Liège, Liège, Belgium. L.Havard@student.ulg.ac.be
Delvenne
P
P
Fraré
P
P
Boniver
J
J
Giannini
S L
SL
D016207:Cytokines / Q000032:analysis*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000032:analysis / Q000235:genetics; D007375:Interleukin-1 / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology*; D016328:NF-kappa B / Q000378:metabolism*; D027383:Papillomaviridae / Q000276:immunology*; D012313:RNA / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics
D016207:Cytokines; D007375:Interleukin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor