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CUTTING EDGE |
Responses During Viral Infection1
*
Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912;
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115; and
Department of Host Defense Research, Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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from NK cells is crucial for resistance. However,
the roles for IL-18 and/or IL-12 in regulating hepatic IFN-
responses, as compared with systemic or splenic responses, have not
been defined. In this report, mice genetically deficient in either
IL-18 or IL-12p35 exhibited up to 95% reductions in systemic and
splenic IFN- responses. Surprisingly, IFN- responses were
preserved in the livers of IL-18-deficient, but not IL-12p35-deficient,
mice. Cytokine requirements for host survival also differed. Under
conditions where mice lacking IL-12p35 exhibited 100% mortality, those
lacking IL-18 survived. Taken together, our results delineate
contrasting compartmental requirements for IL-18 and suggest that
preservation of local, hepatic IFN- production is critical for host
defense during murine cytomegalovirus
challenge. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production from NK cells and is potently synergistic with IL-12 for
this function (3, 4). The importance of IL-18 in immunity
and host defense is only beginning to be appreciated. Human macrophages
have been demonstrated to secrete IL-18 upon influenza A and Sendai
viral infections (5, 6), and administration of IL-18 has
been shown to elicit antiviral effects in vaccinia virus-infected mice
(7). Almost nothing is known about the endogenous
induction and in vivo function of IL-18 during viral infections.
Murine cytomegalovirus
(MCMV)3 is a
hepatotropic herpesvirus that induces endogenous IL-12 and NK
cell-dependent IFN- responses crucial in early defense
(8, 9, 10, 11, 12). IL-12 is required for both systemic and splenic
IFN- responses (11, 12, 13), but little information is
available regarding IL-12 functions in liver or the roles for IL-18 at
any of these sites. Mice genetically deficient in the IL-1
receptor-associated kinase, a signaling molecule shared by the IL-1 and
IL-18 receptors, have impaired systemic IFN- responses to MCMV
infections (14). Recent work from our group has shown that
conditions prohibiting recruitment of IFN--producing NK cells to the
liver compromise host defense and results in mortality even in the
presence of intact systemic and splenic IFN- responses (15, 16). The studies presented here define the induction and
function of IL-18 in defense against MCMV infection and contrasts these
to those of IL-12. Collectively, our results demonstrate that IFN-
responses are differentially regulated at particular sites and that
there are selective and specific requirements for IL-18 as a cofactor
in regulating IFN- responses in some, but not all, host
compartments.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 mice were purchased from Taconic Laboratory Animals and Services (Germantown, NY) and The Jackson Laboratory (Bar Harbor, ME). The former were controls for mice with a targeted disruption of the IL-12p35 gene (13), originally provided by Genetics Institute (Andover, MA); the latter were controls for mice genetically deficient in IL-18 (17). All mice were used between 5 and 12 wk of age, and experiments were conducted in accordance with institutional guidelines for animal care and use.
In vivo treatments and sample collection
Infections were established on day 0 by i.p. injections of
5 x 104 PFU of MCMV v70 Smith strain
(11). In experiments utilizing LPS, mice were treated i.p.
with a 100-µg dose from Escherichia coli strain O111:B4
(Difco, Detroit, MI) for 6 h. At indicated times after injections,
serum and organs were collected. In survival experiments, mice were
infected with 105 PFU of MCMV and assessed for
mortality at least once daily for 
21 days.
Preparation of leukocytes
Splenic and hepatic leukocytes were prepared as described previously (18). For flow cytometric analyses, hepatic populations were isolated by density centrifugation on Percoll gradients. Because cell yields were limiting with this protocol, 24% metrizamide gradients (Accurate Chemical and Scientific, Westbury, NY) were used for preparation of hepatic effector cells used in cytotoxic activity assays (19). Cell yields and viability were determined by trypan blue exclusion.
Cytokine measurements
For determination of cytokine levels, organs were weighed and
homogenized (16). Supernatants were assayed for IFN-,
IL-12p40 (detects p40 plus p70), or IL-18 (detects 24-kDa precursor
plus 18-kDa bioactive species) levels by sandwich ELISA (10, 12). IL-18 ELISA reagents utilized a rat monoclonal Ab (R&D
Systems, Minneapolis, MN) for capture, a goat polyclonal Ab (R&D
Systems), and an anti-goat HRP-conjugated Ab for visualization with
2,2'-azino-di(3-ethyl-benzthiazoline-6-sulfonate) substrate. Standard
curves were generated with recombinant mature murine IL-18 (R&D
Systems).
NK cell flow cytometric analyses, intracellular IFN- staining,
and cytotoxicity assays
Surface and intracellular IFN- protein staining were done as
described previously (18). NK cells were phenotypically
identified as NK1.1+TCR-ß-
populations. For intracellular staining, >100,000 events were
collected using a FACSCalibur (Becton Dickinson, San Jose, CA) with an
argon laser operating at 15 mW at 488 nm and a blue diode laser
operating at 635 nm. Specificity of intracellular IFN-
staining was done by competition with unconjugated XMG1.2 Ab. NK cell
cytotoxic activity against YAC-1 target cells was determined by
standard 51Cr release assays (10, 12).
Plaque assays
To determine MCMV viral titers, serial dilutions of organ homogenates were added to monolayers of NIH 3T3 fibroblast cells. After 1 wk, cells were fixed with 10% buffered Formalin. Plaques were visualized with 0.1% crystal violet and quantitated as log PFU per gram tissue. MCMV standards and negative controls were included in each assay.
Statistical analyses
Data were analyzed using statistical functions and the two-tailed homoscedastic Student’s t test function from Microsoft Excel 98 (Microsoft, Redmond, WA). Unless otherwise indicated, results are given as means ± SEM. Mortality studies were statistically analyzed by the nonparametric Mantel-Cox test from Statview version 4.51 (Abacus Concepts, Berkeley, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Peak systemic and splenic IFN- responses to early MCMV
infection occur 1.5 days after challenge, with hepatic responses
extended through day 2 (16, 20), and IL-12 production in
serum and spleen closely mirrors the kinetics of IFN- induction
(11, 12, 13, 20). The results presented here were consistent
with these observations (Fig. 1
, A–E). Compartmental characterization of IL-12 expression
was extended to include liver, and IL-18 expression was evaluated in
all three compartments for the first time. Hepatic levels of IL-12
peaked on day 1.5 but were slower to subside and were sustained through
day 2 (Fig. 1F). As measured by ELISA, systemic levels of
total IL-18 protein were below the limits of detection in uninfected
mice (Fig. 1G). In contrast, IL-18 was expressed
constitutively in both spleens and livers from uninfected mice. Modest
induction was observed systemically and in both organs on day 1.5 of
infection (Fig. 1, G–I). Western blot analyses revealed
that IL-18 was primarily expressed as precursor, with moderate
induction of mature factor in the spleen on days 1 through 1.5 of
infection (data not shown). In contrast, although levels of precursor
IL-18 were readily detectable in the liver, mature factor was nearly
undetectable. These results show that total IL-18 expression is
sustained more broadly than IL-12 and suggest a dichotomy in which
mature IL-18 is induced to higher levels in the spleen than the liver
after MCMV infection.
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responses
To determine the importance of endogenous IL-12 and IL-18 for
regulating IFN- responses during infection, mice genetically
deficient in either the p35 subunit of IL-12
(IL-12-) or IL-18 (IL-18-) were
examined. Compared with IL-12+ hosts, IL-12-
mice exhibited up to 95% reductions in IFN- responses in serum,
spleen, and liver on day 1.5 (Fig. 2A). Furthermore, the extended
hepatic IFN- kinetics on day 2 were compromised by >85% in the
absence of bioactive IL-12. Total and bioactive IL-18 proteins in
spleens of IL-12- mice were induced to levels comparable
to those of IL-12+ mice (data not shown). Thus,
IL-12 is globally required for driving peak IFN- production
independent of effects on IL-18 protein expression.
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responses in serum and spleen (Fig. 2
B). However, no
significant changes in liver IFN- responses were observed, and the
sustained expression of IFN- on day 2 was also maintained (Fig. 2B). Thus, IL-18 was selectively required for systemic and
splenic IFN- responses, but unlike IL-12, was not required for
induction of IFN- in the liver. Since IL-18+
and IL-18- mice expressed equivalent levels of
IL-12p70 (data not shown), the compartmentally selective deficits in
IFN- responses did not appear to be due to secondary effects on
IL-12 production. The lack of a role for IL-18 in the hepatic response
was contextual. Consistent with other reports (21), in
vivo challenge with LPS for 6 h resulted in >50% reductions in
IFN- responses in all three sites (data not shown). In summary,
IL-18 is necessary for optimal IFN- induction under some conditions,
but is dispensable for innate hepatic IFN- responses during MCMV
infections. NK cell responses in IL-18- and IL-12p35-deficient mice
Because NK phenotype cells have been identified as the source of
early IFN- during MCMV infections (10, 11, 15), NK cell
proportions and numbers were evaluated in IL-18- and
IL-12- mice. Flow cytometric analyses revealed no
significant differences in either proportions or total numbers of NK
(NK1.1+TCR-ß-) cells as
compared with control mice (data not shown). Because the splenic, but
not hepatic, IFN- responses were dependent upon IL-18, intracellular
staining was done to examine the effects of IL-18 deficiency on NK cell
IFN- expression. After 1.5 days of infection, an average of 73% of
NK cells from IL-18+ mice were expressing IFN-
as compared with 50% of NK cells from IL-18-
mice (p < 0.01). Furthermore, mean
fluorescence intensities (MFIs) for splenic NK cell IFN- staining
from IL-18+ and IL-18-
mice were 361 and 163, respectively (p <
0.01). Thus, in the spleen, both the proportions of IFN--producing
NK cells and the levels of IFN- expression were reduced in the
absence of IL-18. In contrast, hepatic NK cells exhibited comparable
proportions and MFIs of intracellular IFN- expression, reaching 39
and 42%, and 80 and 78%, respectively, in
IL-18+ and IL-18- mice.
Thus, the compartmentally selective IL-18 requirement is mediated, at
least in part, at the level of NK cell IFN- expression.
Splenic NK cell cytotoxic activity is IL-12- independent
under these conditions (11, 12). Using IL-12-
mice, these observations were repeated in the spleen and extended to
the liver. Cytolytic activities against YAC-1 target cells sensitive to
NK cell-mediated lysis were found to be comparable between
IL-12+ and IL-12- mice, in
both spleens and livers, after 2 days of MCMV infection (Fig. 3A). Likewise, average
cytotoxic activity was induced to similar levels in both spleens and
livers of control and IL-18- mice (Fig. 3B).
Hence, neither IL-18 nor IL-12 is required for induction of NK cell
cytotoxic activity in either site during MCMV infection.
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Control of hepatic MCMV replication early during infection is
dependent upon NK cells, IL-12, and NK cell-derived IFN-
(9, 10, 11, 12, 16). As the studies presented thus far have
demonstrated a selective compartmental role for IL-18 in IFN-, but
not cytolytic, responses, susceptibility to infection was evaluated in
IL-18+ and IL-18- mice. No
differences in early hepatic viral titers were observed. On day 3 of
infection, viral titers in liver reached 5.2 and 4.9 log PFU/g tissue
in IL-18+ and IL-18- mice,
respectively. Day 3 viral titers were also comparable in the spleen,
respectively, reaching 5.1 and 4.9 log PFU/g tissue. In host survival
studies challenging mice with 105 PFU of MCMV,
all immunocompetent and IL-18- mice survived
beyond 21 days at this infecting dose of virus (Fig. 4). In contrast,
IL-12- mice exhibited 100% mortality by day 8
of infection (Fig. 4). Taken together, these results demonstrate that
under comparable conditions of MCMV infection, IL-18 is dispensable,
but IL-12 is critical, for host survival.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-12, and IL-18
in the sera, spleens, and livers of MCMV-infected mice. The results
demonstrate that although IL-12 is required for driving IFN-
responses in all three compartments, IL-18 is only necessary for
systemic and splenic responses. This compartmentally selective deficit
in IFN- production is observable as reductions in proportions and
total numbers of IFN--expressing NK cells from the spleen with
concomitant maintenance of expression in hepatic NK cells. The deficit
is also functionally specific, as control and
IL-18- mice have comparable NK cell proportions
and total numbers, as well as comparable induction of cytotoxic
activity in both spleen and liver following infection. Although
IL-18- mice exhibit a compartmentally selective
deficit in IFN- responses, these mice do not succumb to infection,
whereas IL-12- mice are highly susceptible. Taken
together, our data conclusively define a compartmental role for IL-18
in regulating in vivo NK cell IFN- responses, but suggest that the
role may not be critical for defense against this viral infection.
The work extends our understanding of the importance of local immune
responses. Our group has recently demonstrated that in
macrophage-inflammatory protein 1
-deficient mice, NK cells fail to
traffick to the liver after MCMV infection (15, 16). As a
result, hepatic IFN- responses are severely reduced.
Macrophage-inflammatory protein 1-deficient mice succumb to the
infection despite the preservation of systemic and splenic IFN-
expression (16). Conversely in the studies presented here,
IL-18- mice survive despite compromised
responses systemically and in the spleen (Fig. 4). Since
IL-18- mice have intact responses in the liver, the
studies collectively suggest that the liver may be the critical
battleground for host defense against infections by hepatotropic MCMV.
Although splenic IFN- expression, but not cytotoxic activity, was
greatly diminished in IL-18- mice, viral titers
were not elevated compared with control mice. This is consistent with a
report in which control of viral replication in the spleen is proposed
to be dependent upon perforin but not IFN- (22). Our
results, however, also suggest that preservation of early antiviral
IFN- responses in the liver is necessary for host survival, whereas
splenic cytotoxicity is insufficient because an IL-12 deficiency
results in death despite preserved cytotoxic function in both spleen
and liver (Fig. 3).
The lack of requirement for IL-18 in the liver during MCMV infection is
intriguing, particularly because this cytokine was originally purified
from the livers of mice challenged with bacterial products
(23) and has a role in LPS-induced IFN- responses in
all three compartments. The dispensability of IL-18 may be the result
of other, as yet unidentified, costimulatory interactions involved in
regulating hepatic IFN- responses. As hepatic NK cells colocalize at
sites of IFN- and viral Ag expression (15), NK cells
may receive additional cell-matrix and/or cell-cell contact signals to
promote IL-12-driven IFN- production locally. These signals could be
delivered during the initial migration into hepatic sinusoids where
integrins may supply a necessary costimulus (24) and/or
within inflammatory foci through contact with cells expressing
particular costimulatory molecules (25, 26, 27).
Although both IL-12 and IL-18 have been shown to be capable of
augmenting NK cell cytotoxic activity in other settings (17, 23), during MCMV infections this effector function is induced
independently of either cytokine (Fig. 3), but does require IFN-ß,
at least in the spleen (11, 12). Thus, there is a
dichotomy between what panel of functions a specific cytokine can
potentially mediate and which subsets of those functions are actually
accessed in vivo during viral infections. The results also show that
dichotomy of cytokine function is further regulated at the
compartmental level, such that local cytokine requirements for
induction of IFN- can vary from site to site. This schema is likely
in place to afford the host a measure of fine tuning, such that
potentially beneficial factors are locally regulated to allow access to
antiviral pathways in some compartments while simultaneously limiting
possible deleterious effects in others.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Christine A. Biron, Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Box G-B629, Brown University, Providence, RI 02912.
3 Abbreviations used in this paper: MCMV, murine cytomegalovirus; MFI, mean fluorescence intensity.
Received for publication August 11, 2000. Accepted for publication August 25, 2000.
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M. M. Gherardi, J. C. Ramirez, and M. Esteban IL-12 and IL-18 act in synergy to clear vaccinia virus infection: involvement of innate and adaptive components of the immune system J. Gen. Virol., August 1, 2003; 84(8): 1961 - 1972. [Abstract] [Full Text] [PDF]
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M. Strengell, S. Matikainen, J. Siren, A. Lehtonen, D. Foster, I. Julkunen, and T. Sareneva IL-21 in Synergy with IL-15 or IL-18 Enhances IFN-{gamma} Production in Human NK and T Cells J. Immunol., June 1, 2003; 170(11): 5464 - 5469. [Abstract] [Full Text] [PDF]
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0.01), and between IL-18+ and
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