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,
,§
*
Lineberger Comprehensive Cancer Center,
Department of Medicine,
Department of Microbiology and Immunology, and
§
Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599
To continue our investigation of the cellular events that occur
following human CMV (HCMV) infection, we focused on the regulation of
cellular activation following viral binding to human monocytes. First,
we showed that viral binding induced a number of immunoregulatory genes
(IL-1ß, A20, NF-
B-p105/p50, and IB
) in unactivated monocytes
and that neutralizing Abs to the major HCMV glycoproteins, gB (UL55)
and gH (UL75), inhibited the induction of these genes. Next, we
demonstrated that these viral ligands directly up-regulated monocyte
gene expression upon their binding to their appropriate cellular
receptors. We then investigated if HCMV binding also resulted in the
translation and secretion of cytokines. Our results showed that HCMV
binding to monocytes resulted in the production and release of IL-1ß
protein. Because these induced gene products have NF-B sites in
their promoter regions, we next examined whether there was an
up-regulation of nuclear NF-B levels. These experiments showed that,
in fact, NF-B was translocated to the nucleus following viral
binding or purified viral ligand binding. Changes in IB levels
correlated with the changes in NF-B translocation. Lastly, we
demonstrated that p38 kinase activity played a central role in IL-1ß
production and that it was rapidly up-regulated following infection.
These results support our hypothesis that HCMV initiates a signal
transduction pathway that leads to monocyte activation and pinpoints a
potential mechanism whereby HCMV infection of monocytes can result in
profound pathogenesis, especially in chronic inflammatory-type
conditions.
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Z. Tabi, M. Moutaftsi, and L. K. Borysiewicz Human Cytomegalovirus pp65- and Immediate Early 1 Antigen-Specific HLA Class I-Restricted Cytotoxic T Cell Responses Induced by Cross-Presentation of Viral Antigens J. Immunol., May 1, 2001; 166(9): 5695 - 5703. [Abstract] [Full Text] [PDF]
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 T. H. Mogensen and S. R. Paludan Molecular Pathways in Virus-Induced Cytokine Production Microbiol. Mol. Biol. Rev., March 1, 2001; 65(1): 131 - 150. [Abstract] [Full Text] [PDF]
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R. A. Johnson, S.-M. Huong, and E.-S. Huang Activation of the Mitogen-Activated Protein Kinase p38 by Human Cytomegalovirus Infection through Two Distinct Pathways: a Novel Mechanism for Activation of p38 J. Virol., February 1, 2000; 74(3): 1158 - 1167. [Abstract] [Full Text]
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K. A. Simmen, J. Singh, B. G. M. Luukkonen, M. Lopper, A. Bittner, N. E. Miller, M. R. Jackson, T. Compton, and K. Fruh Global modulation of cellular transcription by human cytomegalovirus is initiated by viral glycoprotein B PNAS, June 19, 2001; 98(13): 7140 - 7145. [Abstract] [Full Text] [PDF]
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 M. K. Froberg, A. Adams, N. Seacotte, J. Parker-Thornburg, and P. Kolattukudy Cytomegalovirus Infection Accelerates Inflammation in Vascular Tissue Overexpressing Monocyte Chemoattractant Protein-1 Circ. Res., December 7, 2001; 89(12): 1224 - 1230. [Abstract] [Full Text] [PDF]
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