Department of Medical Microbiology and Immunology, The Bartholin Building, University of Aarhus, DK-8000 Aarhus C, Denmark
Correspondence
Søren Paludan
srp{at}microbiology.au.dk
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ABSTRACT |
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MAIN TEXT |
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The host reaction to infection is a highly regulated response aimed at eliminating the infectious agent from the organism. Cytokines are soluble secreted factors that play important roles in regulation of the immune response. With respect to virus infections, the interferons (IFNs), a special subset of cytokines, have been ascribed particularly important roles (Muller et al., 1994; Mikloska & Cunningham, 2001
; Salazar-Mather et al., 2002
). IFN-
/
, or type I IFNs, are produced rapidly after infection (Ellermann-Eriksen, 1993
; Malmgaard et al., 2002
) and form part of the very first line of defence (Stark et al., 1998
). IFN-
is produced both in the early stages of infection by natural killer cells and at later stages by activated T cells (Boehm et al., 1997
). IFN-
is a strong activator of macrophages (Boehm et al., 1997
; Paludan et al., 1998
; Malmgaard et al., 2000
) and is also involved in driving the development of CD4+ T cells towards a Th1 response (Boehm et al., 1997
). Not surprisingly, IFN-
is crucial for elimination of many virus infections, including HSV infections (Kodukula et al., 1999
; Harandi et al., 2001
; Mikloska & Cunningham, 2001
). In this work, we have investigated how expression of IFN-
is regulated during the early stages of HSV infection in a peritoneal cell culture system containing a mixture of leukocytes.
In order to examine how IFN- production is regulated during HSV-2 infection, we first examined the expression of IFN-
/
, interleukin (IL)-12 and IL-18, all cytokines reported to play a role in the regulation of IFN-
production (Orange & Biron, 1996
; Nakamura et al., 1989
; Pien et al., 2000
; Nguyen et al., 2002
). Thioglycolate-elicited peritoneal cells (PCs) were harvested from the peritoneal cavity of 8-week-old female BALB/c mice and cultured in RPMI 1640 medium supplemented with 5 % foetal calf serum (Bio-Whittaker). The following day, the cells were infected with the MS strain of HSV-2 (3x106 p.f.u. ml-1) and incubated for different intervals up to 24 h at 37 °C. Supernatants were harvested and cytokine levels measured by ELISA (IL-12, IL-18 and IFN-
) or bioassay (IFN-
/
). As seen in Fig. 1
(a), IFN-
/
production was induced within 4 h of infection. IL-12p40 was also induced by HSV-2 infection with a significant increase observed after 8 h of infection (Fig. 1b
). For both cytokines, the levels increased continuously throughout the 24 h of the experiment. IL-18 was produced constitutively in amounts well above the detection limit (Fig. 1c
) and HSV-2 infection did not affect the production of IL-18 in PCs. This finding, however, does not exclude enhanced IL-18 signalling following HSV-2 infection, since we have previously reported that expression of both the IL-18 receptor and the pro-IL-18-cleaving enzyme caspase-1 are induced by HSV (Paludan et al., 2002
). In order to correlate the induction of IFN-
with expression of the cytokines shown in Fig. 1(ac), we also examined the kinetics of expression of IFN-
. Interestingly, accumulation of IFN-
was detectable after 12 h of HSV-2 infection (Fig. 1d
) and hence occurred with delayed kinetics compared with IFN-
/
and IL-12. These findings therefore indicate a possible role for these cytokines in HSV-2-induced IFN-
expression.
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ACKNOWLEDGEMENTS |
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Received 24 March 2003;
accepted 13 May 2003.
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