Journal of Virology, November 2001, p. 10170-10178, Vol. 75, No. 21
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.21.10170-10178.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Department of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark
Received 28 March 2001/Accepted 30 July 2001
Macrophages respond to virus infections by rapidly secreting
proinflammatory cytokines, which play an important role in the first
line of defense. Tumor necrosis factor alpha (TNF-
) is one of the
major macrophage-produced cytokines. In this study we have
investigated the virus-cell interactions responsible for induction of
TNF-
expression in herpes simplex virus (HSV)-infected macrophages.
Both HSV type 1 (HSV-1) and HSV-2 induced TNF-
expression in
macrophages activated with gamma interferon (IFN-
). This induction was to some extent sensitive to UV treatment of the virus. Virus particles unable to enter the cells displayed reduced capacity to
stimulate TNF-
expression but retained a significant portion which
was abolished by HSV-specific antibodies. Recombinant HSV-1 glycoprotein D was able to trigger TNF-
secretion in concert with
IFN-
. Sugar moieties of HSV glycoproteins have been reported to be
involved in induction of IFN-
but did not contribute to TNF-
expression in macrophages. Moreover, the entry-dependent portion of the
TNF-
induction was investigated with HSV-1 mutants and found to be
independent of the tegument proteins VP16 and UL13 and partly dependent
on nuclear translocation of the viral DNA. Finally, we found that
macrophages expressing an inactive mutant of the double-stranded RNA
(dsRNA)-activated protein kinase (PKR) produced less TNF-
in
response to infectious HSV infection than the empty-vector control cell
line but displayed the same responsiveness to UV-inactivated virus.
These results indicate that HSV induces TNF-
expression in
macrophages through mechanisms involving (i) viral glycoproteins, (ii)
early postentry events occurring prior to nuclear translocation of
viral DNA, and (iii) viral dsRNA-PKR.
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