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Doctoral Thesis
DOI
10.11606/T.46.2002.tde-06022009-150450
Document
Author
Full name
Enrique Mario Boccardo Pierulivo
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2002
Supervisor
Committee
Villa, Luisa Lina (President)
Armelin, Hugo Aguirre
Linden, Rafael
Quaggio, Ronaldo Bento
Strauss, Bryan Eric
Title in Portuguese
Efeito do fator de necrose tumoral-alfa (TNF-α)sobre células imortalizadas por papilomavírus humano (HPV)
Keywords in Portuguese
Culturas organotípicas
Doenças infecciosas (Estudo)
E7
HPV
Imortalização
Neoplasias (Virologia)
Queratinócitos
TNF
Abstract in Portuguese
A infecção por papilomavírus humano (HPV) é o principal fator de risco para o desenvolvimento de neoplasias intra-epiteliais cervicais, as lesões precursoras do carcinoma da cérvice uterina. O fator de necrose tumoral-α (TNF-α) é um dos principais mediadores da inflamação da pele e das mucosas. Esta citocina é capaz de inibir a proliferação de queratinócitos normais e imortalizados por HPV-16. Por outro lado, queratinócitos imortalizados por HPV-18 ou transformados por HPV 16 ou 18 são resistentes aos efeitos do TNF-α. Entretanto, a base molecular desta diferença ainda é pouco conhecida. No presente estudo observamos o aumento dos níveis do inibidor de quinases p21, diminuição dos níveis de ciclina A e a ativação do fator NF-κB após tratamento com TNF-α, apenas em células sensíveis à citocina. Por outro lado não foi observada alteração dos níveis de p16, p27, p65, ciclinas D1, E e CDKs -4 e -6 em nenhuma das linhagens estudadas. Culturas organotípicas (rafts) de queratinócitos normais apresentaram uma acentuada inibição da proliferação após o tratamento com TNF-α. Isso não foi observado em rafts de queratinócitos infectados com o genoma completo de HPV-18. Entretanto, as culturas organotípicas transduzidas com vetores retrovirais contendo o gene viral E7 apresentaram um fenótipo intermediário, indicando que a proteína E7 desempenha um papel na resistência a esta citocina.
Title in English
Effects of tumor necrosis factor-alpha (TNF-α) on HPV - immortalized cells
Keywords in English
E7
HPV
Immortalization
Infectious diseases
Keratinocytes
Neoplasia (Virology)
Organotypic ultures
TNF
Abstract in English
Infection by Human papillomavirus (HPV) is the major etiologic factor in the development of cervical intra-epithelial neoplasia, the precursor of carcinoma of the uterine cervix. Tumor necrosis factor-alpha (TNF-α) is one of the main mediators of skin and mucosa inflamation and has a potent anti-proliferative effect on normal and HPV16 immortalized keratinocytes. On the other hand, HPV-18 immortalized and HPV-16 or -18 transformed keratinocytes are resistant to TNF-α. However the molecular basis of this difference is not well understood. In the present study we observed and increase in the CDK inhibitor p21, reduced levels of cyclin A and activation of NF-κB factor only in cells sensitive to this cytokine. Conversely, no alterations in the p16, p27, p65, cyclins D1, E and CDKs -4 and -6 levels was observed in any of the cell lines analyzed. Proliferation of normal primary human keratinocytes (PHK) raft cultures was markedly inhibited after treatment with TNF-α. This was not observed in cultures transfected with HPV-18 whole genome. Cultures transduced retroviral vectors carrying the E7 viral gene showed an intermediate phenotype suggesting that this protein contribute to TNF-α resistance.
 
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Publishing Date
2009-03-03
 
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