Faculty Collaboration Database

Macrophages kill human papillomavirus type 16 E6-expressing tumor cells by tumor necrosis factor alpha- and nitric oxide-dependent mechanisms. J Virol 2005 Jan;79(1):116-23

Date

12/15/2004

Pubmed ID

15596807

Pubmed Central ID

PMC538740

DOI

10.1128/JVI.79.1.116-123.2005

Scopus ID

2-s2.0-10644279845 (requires institutional sign-in at Scopus site)   32 Citations

Abstract

The expression of adenovirus serotype 2 or 5 (Ad2/5) E1A sensitizes cells to killing by NK cells and activated macrophages, a property that correlates with the ability of E1A to bind the transcriptional coadaptor proteins p300-CBP. The E6 oncoproteins derived from the high-risk human papillomaviruses (HPV) interact with p300 and can complement mutant forms of E1A that cannot interact with p300 to induce cellular immortalization. Therefore, we determined if HPV type 16 (HPV16) E6 could sensitize cells to killing by macrophages and NK cells. HPV16 E6 expression sensitized human (H4 and C33A) and murine (MCA-102) cell lines to lysis by macrophages but not by NK cells. The lysis of cells that expressed E6 by macrophages was p53 independent but dependent on the production of tumor necrosis factor alpha (TNF-alpha) or nitric oxide (NO) by macrophages. Unlike cytolysis assays with macrophages, E6 expression did not significantly sensitize cells to lysis by the direct addition of NO or TNF-alpha. Like E1A, E6 has been reported to sensitize cells to lysis by TNF-alpha by inhibiting the TNF-alpha-induced activation of NF-kappaB. We found that E1A, but not E6, blocked the TNF-alpha-induced activation of NF-kappaB, an activity that correlated with E1A-p300 binding. In summary, Ad5 E1A and HPV16 E6 sensitized cells to lysis by macrophages. Unlike E1A, E6 did not block the ability of TNF-alpha to activate NF-kappaB or sensitize cells to lysis by NK cells, TNF-alpha, or NO. Thus, there appears to be a spectrum of common and unique biological activities that result as a consequence of the interaction of E6 or E1A with p300-CBP.

Author List

Routes JM, Morris K, Ellison MC, Ryan S

Author

John M. Routes MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cell Death
Cell Line, Tumor
Humans
Killer Cells, Natural
Macrophage Activation
Macrophages
Mice
Nitric Oxide
Oncogene Proteins, Viral
Repressor Proteins
Tumor Necrosis Factor-alpha