Download Interleukin-18 improves the early defence system against influenza

Journal of General Virology (2004), 85, 423–428
DOI 10.1099/vir.0.19596-0
Interleukin-18 improves the early defence system
against influenza virus infection by augmenting
natural killer cell-mediated cytotoxicity
Beixing Liu,1 Isamu Mori,1 Md Jaber Hossain,1 Li Dong,1 Kiyoshi Takeda2
and Yoshinobu Kimura1
1
Department of Microbiology, Fukui Medical University School of Medicine, Shimoaisuki 23-3,
Matsuoka-cho, Yoshida-gun, Fukui 910-1193, Japan
Correspondence
Yoshinobu Kimura
[email protected]
Received 25 August 2003
Accepted 7 October 2003
2
Research Institute for Microbial Diseases, Osaka University, Suita 565-0871, Japan
The role of interleukin (IL)-18 in the development of the host defence system against influenza
virus infection was investigated. IL-18-deficient (IL-18”/”) C57BL/6 mice that were inoculated
intranasally with the mouse-adapted strain of human influenza A/PR/8/34 (H1N1) virus showed an
increased mortality with the occurrence of pathogenic changes in the lung for the first 3 days
of infection, which included pronounced virus growth with massive infiltration of inflammatory
cells and elevated nitric oxide production. The interferon-gamma (IFN-c) level induced in the
respiratory tract of IL-18”/” mice in the first few days after virus infection was significantly lower
but, in contrast, the IL-12 level was slightly higher than the corresponding levels in wild-type
C57BL/6 mice. Natural killer (NK) cell-mediated cytotoxicity in the lung of IL-18”/” mice was
poorly activated. Local immune responses in the lung such as specific cytotoxic T lymphocyte
and antibody production were induced upon influenza virus infection equally well in both strains
of mice. These results indicate that IL-18 is involved in controlling influenza virus replication in
the lung, especially at an early stage of infection, through activation of the innate immune
mechanisms such as IFN and NK cells.
INTRODUCTION
Influenza virus attacks a large proportion of the population every year and can cause death, especially among
older people, infants and immunocompromised individuals (Brody & Brock, 1985; Glezen et al., 1980). The
immunocompetent cell system with a network of cytokines
and chemokines induces protective immunity against
influenza virus infection (Ryan et al., 2002; Van Reeth
et al., 2002). Interleukin (IL)-18, previously considered to
be an interferon-gamma (IFN-c)-inducing factor, is synthesized by activated macrophages and shows similar
properties to IL-1 in biochemical functions and to IL-12
in biological functions (Dinarello, 1999; Okamura et al.,
1998). This cytokine plays a critical role in the development of protective immunity against intracellular pathogens
including Mycobacterium tuberculosis, Yersinia enterocolitica, Cryptococcus neoformans and herpes simplex virus
(Bohn et al., 1998; Fujioka et al., 1999; Kawakami et al.,
1997; Sugawara et al., 1999). The protective role of IL-18
is attributable to its ability to induce IFN-c production, to
activate natural killer (NK) cells and to proliferate activated
T lymphocytes (Takeda et al., 1998). We have reported that
IL-18 plays a key role in activating microglial functions
by inducing neuronal IFN-c in the brain parenchyma
following neurovirulent influenza A virus infection in the
0001-9596 G 2004 SGM
olfactory bulb (Mori et al., 2001). However, knowledge
is scarce about the relationship between the host defence
system in the respiratory tract and the role of endogenous
IL-18 during influenza virus infection. IL-18 mRNA has
been found to be constitutively expressed within the lung,
mostly localized in the respiratory epithelial cells (Cameron
et al., 1999). Influenza virus principally causes surface
infection that is restricted to mucosal cells of the respiratory tract. Therefore, it is interesting to investigate whether
IL-18 is a critical mediator for establishment of the primary
defence system against influenza virus infection.
In the present study, we infected IL-18-gene disrupted
(IL-182/2) mice with influenza A virus intranasally and
investigated the host defence mechanism, particularly
focusing on the local responses in the respiratory tract.
The response of the wild-type C57BL/6 mice to influenza
virus infection was used as a control.
METHODS
Virus. The mouse-adapted strain of human influenza virus A/PR/8/
34 (H1N1) was propagated routinely by allantoic inoculation of 10day-old embryonated chicken eggs with seed virus diluted 1 : 1024.
Virus titre was assayed by plaque titration on Madine–Darby canine
kidney cell monolayers, as described elsewhere (Mori et al., 1995).
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B. Liu and others
Mice. IL-182/2 mice, with the genetic background of C57BL/6
mice, were generated by the gene targeting method (Takeda et al.,
1998). The mice were bred and maintained in the Animal
Laboratory of Fukui Medical University under specific pathogen-free
conditions. The concentration of IL-18 molecules in serum from
IL-182/2 mice, measured by ELISA, was below the detectable level
(cf. 1000±20 pg ml21 in normal C57BL/6 mice). This indicated
that the IL-18 gene mutation leads to a lack of IL-18 production.
Six-week-old IL-182/2 mice and age-matched C57BL/6 mice (Clea
Japan) were used for the experiments.
Experimental infections. Mice were mildly anaesthetized by intra-
peritoneal administration of pentobarbital sodium (0?025 mg g21
body mass) and inoculated in the right nostril with influenza A
virus in 20 ml sterile PBS. To avoid laboratory contamination, all
virus-infected mice were housed in negatively pressurized isolators
equipped with a ventilation system through a high-efficiency particulate air filter (AH model; Nihon-Ika). This work was approved
by the Committee of Institutional Animal Care and Use in Fukui
Medical University.
Preparation of single-cell suspensions from the lung parenchyma. Mice were anaesthetized and the lung was flushed in situ
with 20 ml sterile PBS via cannulation of the heart to remove the
intravascular blood pool. Minced lung tissues were incubated at
37 uC for 60 min on a rocker with 200 mg collagenase D ml21 and
40 mg DNase I ml21 (both from Roche Molecular Biochemicals).
Subsequently, the enzyme-digested lung tissue was passed through a
stainless steel mesh. Single-cell suspensions were collected by densitygradient centrifugation with lymphocyte separation solution (Antibody
Institute).
Identification of lung parenchyma cells. Single-cell suspensions
from the lung parenchyma were identified by flow cytometry (EPCS
XL, Beckman Coulter) using monoclonal antibodies for CD4, CD8,
CD16/32 and neutrophil (Caltag).
RESULTS
Susceptibility of IL-18”/” mice to influenza virus
infection
To elucidate the role of IL-18 molecules in host defence
mechanisms against influenza virus infection, mice were
inoculated intranasally with 103 p.f.u. influenza A/PR/8/34
virus per mouse and the time course of mortality was
investigated. Seventeen per cent of virus-infected IL-182/2
mice died within the observation period of 15 days, while
all wild-type C57BL/6 mice survived the infection (Fig. 1a).
When the inoculum dose was increased to 104 p.f.u. per
mouse, the overall survival rate was 33 % for IL-182/2 and
50 % for wild-type mice (Fig. 1b). The LD50 of influenza
virus was calculated as 103?7 p.f.u. for IL-182/2 mice and
104 p.f.u. for wild-type mice. The difference in the mortality
between the IL-182/2 and the wild-type mice was at no
point statistically significant. Virus growth in the lungs
of IL-182/2 mice reached the maximum more quickly,
peaking at day 3, with a significantly higher virus titre
than that of wild-type mice (Fig. 2). The progeny virus
was eventually cleared from the lungs of both IL-182/2 and
wild-type mice by day 12 after virus inoculation.
Inflammation in the lungs of IL-18”/” mice
Single-cell suspensions were collected from the lungs and
identified using specific antibodies for cell markers. A large
Assay of cytokine and nitric oxide production in the BAL
fluids. The amounts of cytokines such as IFN-c, IL-12 and IL-4
were assayed by using a mouse cytokine detection ELISA kit
(BioSource) as described previously (Liu et al., 2003). The minimum
detectable concentrations of IFN-c, IL-12 and IL-4 were 1 pg ml21,
2 pg ml21and 5 pg ml21, respectively. The level of nitric oxide was
measured with a Nitric Oxide Assay kit (Calbiochem-Novabiochem),
in accordance with the manufacturer’s instructions.
Assay of NK cell and cytotoxic T lymphocyte (CTL) activities
in the lung parenchyma. A cytotoxicity assay was performed
according to the protocol previously described (Liu et al., 2001).
Lung parenchyma cells and NK-sensitive Yac-1 target cells were
mixed and incubated at 37 uC in a 5 % CO2 atmosphere for 4 h.
Specific lysis of target cells was determined by a lactate dehydrogenase release assay (Decker & Lohmann-Matthes, 1988) using a
Cytotoxic Detection kit (Roche). Data were expressed as the
percentage of specific release: 1006[(target with effector 2 effector
spontaneous) 2 target spontaneous]/[target maximum 2 target
spontaneous]. For the assay of specific CTL activity, target cells were
prepared using mouse lymphoma EL-4 cells infected with influenza
A virus at an input m.o.i. of 10 p.f.u. per cell.
Antibody assay. Virus-specific immunoglobulins (Igs) were measured
with an ELISA Ig Quantitative kit (Bethyl Laboratories) as described
previously (Dong et al., 2003). Bronchoalveolar lavage (BAL) fluids
and sera were collected and assayed for a T helper type 2 (Th2)-related
antibody, IgG1, and for a Th1-related antibody, IgG2a.
Statistical significance. The two-tailed Mann–Whitney U-test
and Student’s t-test were used to determine whether a significant difference (P<0?05) existed between IL-182/2 and control C57BL/6 mice.
424
Fig. 1. Survival profiles of IL-18-deficient ($) and wild-type
C57BL/6 (#) mice after intranasal infection with influenza
A/PR/8/34 virus at an inoculum dose of 103 (a) and 104 (b)
p.f.u. per mouse (n=12).
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Journal of General Virology 85
Role of IL-18 in influenza virus infection
Fig. 2. Pulmonary virus growth in IL-18-deficient (filled bar)
and wild-type C57BL/6 (open bar) mice after intranasal inoculation with influenza A virus at an inoculum dose of 103 p.f.u.
per mouse. Data are means±SD of results for each group of
six mice tested. *, Significant difference compared with corresponding wild-type C57BL/6 mice (P<0?01).
2/2
number of cells infiltrated the lung parenchyma of IL-18
mice during the early phase of infection (Fig. 3). The cell
population in the lungs consisted mostly of neutrophils
(Table 1). Large quantities of nitric oxide could be detected
in BAL fluids immediately after infection (Fig. 4a). In sera,
larger amounts of nitric oxide appeared on day 2 and quickly
vanished on day 3 (Fig. 4b), giving a possible reason for
severe respiratory damage. The dominant inflammatory
reaction in IL-182/2 mice at this time point after infection
was correlated with a large amount of virus loading in the
lung parenchyma (Fig. 2). It should be noted that the
number of T lymphocytes positive for CD4 or CD8 did not
differ between the two strains of mice (Table 1).
Effect of IL-18 molecules on local cytokine
production
Mice were infected with influenza virus intranasally and
BAL fluids were collected and assayed for IFN-c, IL-12 and
Fig. 3. Cellular infiltration in the lung of IL-18-deficient (filled
bar) and wild-type C57BL/6 (open bar) mice after intranasal
infection with influenza A virus at an inoculum dose of
103 p.f.u. per mouse. Data are means±SD of results for each
group of six mice tested. *, Significant difference compared
with corresponding wild-type C57BL/6 mice (P<0?01).
IL-4 titres. IFN-c production in wild-type C57BL/6 mice
was increased for the first 3 days of infection, while in
IL-182/2 mice only a slight increase in titre could be
detected (Fig. 5). In contrast to IFN-c, IL-182/2 mice produced larger amounts of IL-12 upon infection compared
with wild-type mice. The level of IL-4, a Th2 cytokine, was
not detectable until 9 days after infection, at which time a
very low titre was measured in both strains of mice.
NK cell activity of lung parenchyma cells
During an early stage of infection, before the appearance of
the specific immune responses, NK cell activity is the major
factor that contributes to a rapid termination of virus
infection. As anticipated, lung parenchyma cells from
IL-182/2 mice showed a lower level of activity of NK
cell-mediated cytolysis than those from wild-type mice
(Fig. 6). This finding indicated that IL-18 is essential for
full development of NK cell activity during the early days
of infection.
Table 1. Distribution of cell populations in the lung of IL-18-deficient (IL-18”/”) and wild-type
C57BL/6 mice
Mice were infected intranasally with influenza virus at an inoculum dose of 103 p.f.u. per mouse. Lung
cells were collected on day 2 after infection and analysed by flow cytometry. Data are means±SD of
results for each group of six mice tested.
Mouse
strain
IL-18
2/2
C57BL/6
Virus
infection
Before
After
Before
After
No. of cells (6105)
CD4
0?6±0?1
0?7±0?3
0?5±0?1
0?6±0?4
CD8
CD16/32
Neutrophil
Others
0?3±0?1
0?5±0?2
0?2±0?1
0?8±0?3
1?7±0?6
3?1±1?6
1?4±0?5
2?1±0?7
0?2±0?3
5?1±1?4*
0?3±0?2
1?2±0?5
1?8±0?3
1?9±0?4
1?6±0?2
1?3±0?8
*Significantly different compared with corresponding wild-type C57BL/6 mice (P<0?01).
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B. Liu and others
Fig. 4. Induction of nitric oxide in (a) bronchoalveolar lavage
fluids and (b) sera of IL-18-deficient (filled bar) and wild-type
C57BL/6 (open bar) mice after influenza A virus infection. Data
are means±SD of results for each group of six mice tested.
Fig. 5. Cytokine production in the bronchoalveolar lavage fluid
of IL-18-deficient (filled bar) and wild-type C57BL/6 (open bar)
mice after intranasal inoculation with influenza A virus at an
inoculum dose of 103 p.f.u. per mouse. At intervals after infection, the bronchoalveolar lavage fluids were collected and
assayed for (a) IFN-c, (b) IL-12 and (c) IL-4. Data are
means±SD of results for each group of six mice tested.
*, Significant difference compared with corresponding wild-type
C57BL/6 mice (P<0?01).
Specific humoral and cellular immunity in
IL-18”/” mice
Specific Th2-related IgG1 and Th1-related IgG2a antibody
was produced in both BAL fluids and sera of IL-182/2 mice
upon influenza virus infection (Table 2). The antibody
titres were equivalent to those of wild-type mice. In addition, the level of virus-specific CTL activity induced in the
lung of IL-182/2 mice was comparable with the level in
wild-type mice (Table 2). These results suggested that
the IL-18 molecule has no appreciable influence on the
induction of ordinary immune responses.
DISCUSSION
IL-18 was originally described as a factor for IFN-c production of T lymphocytes in the presence of IL-12. Recent
studies have demonstrated that IL-18 shows many other
biological activities, including proliferation of T lymphocytes and NK cells, stimulation of their cytotoxic activity
and enhancement of a Th1-mediated immune response
(Akira, 2000; Dinarello, 1999; Kohno et al., 1997). On the
other hand, IL-18 acts as a proinflammatory cytokine and
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Fig. 6. Natural killer cell activity of the lung cells from influenza
A virus-infected IL-18-deficient ($) and wild-type C57BL/6
(#) mice at the effector to target cell ratio of 50 : 1. Data
are means±SD of results for each group of six mice tested.
*, Significant difference compared with corresponding wild-type
C57BL/6 mice (P<0?01).
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Journal of General Virology 85
Role of IL-18 in influenza virus infection
Table 2. Influenza virus-specific local immune responses in IL-18-deficient (IL-18”/”) and wild-type C57BL/6 mice
Mice were infected intranasally with influenza A virus at an inoculum dose of 103 p.f.u. per mouse. The bronchoalveolar lavage (BAL)
fluids and sera were collected 3 weeks after infection and assayed for influenza virus-specific antibody by ELISA. Antibody titres
(log ng ml21) of IL-182/2 and C57BL/6 mice before virus infection were less than 0?6 in BAL and less than 1?3 in serum. Influenza virusspecific cytotoxic T lymphocyte (CTL) activity on day 9 after infection was determined. Data are means±SD of results for each group of
six mice tested.
Antibody titre (log ng ml”1)
Mouse strain
BAL
IL-182/2
C57BL/6
CTL cytolysis (%)
Serum
Effector to target cell ratio
IgG1
IgG2a
IgG1
IgG2a
50 : 1
25 : 1
12?5 : 1
6?25 : 1
3?4±0?8
3?2±0?6
3?1±0?3
2?8±0?6
4?9±0?6
5?4±0?7
3?8±0?1
4?9±0?1
36?7±6?7
46?7±11?2
23?5±8?9
30?1±10?7
11?3±4?6
18?4±5?2
4?9±3?2
5?7±3?8
increases the severity of diseases with lethal endotoxaemia
(Dinarello, 2000; Lauw et al., 1999; Netea et al., 2000).
Importantly, IL-18 elicits antiviral activity in the acute
phase of infection. In the case of vaccinia virus infection,
IL-18 is involved in various host defence mechanisms,
including NK cells and CTLs (Tanaka-Kataoka et al., 1999).
In fact, virus-induced IL-18 and IFN-c enhance Fas ligand
expression on NK cells (Tsutsui et al., 1996) and Fas
molecules on virus-infected cells (Takizawa et al., 1993).
The results presented in this paper show that, during the
early stage of influenza virus infection, just before the
appearance of specific immune responses, the reduced NK
activity of lung parenchyma cells in IL-182/2 mice was
correlated with profound virus growth in the lung. Thus,
IL-18 plays an important role in the early antiviral host
response by up-regulation of the NK cell-mediated killing
activity of virus-infected cells. A similar early antibacterial
action of IL-18 has also been found during Streptococcus
pneumoniae infection (Lauw et al., 2002).
IFN has long been recognized as an essential part of the
innate cytokine response to virus infection (Hennet et al.,
1992), showing immunomodulatory activity as well as
direct antiviral activity. During the process of IFN-c
production, IL-18 acts in synergy with IL-12 (Kohno et al.,
1997). It is interesting to note that, despite the high titre of
IL-12 induced in IL-182/2 mice, production of IFN-c was
still at a low level (Fig. 5). This finding implies that IL-12
alone, in the absence of IL-18, is insufficient for activation
and development of IFN-c production in vivo and that
functions operated by IL-18 molecules cannot fully be
compensated by IL-12. The major cell population responsible for IFN-c production by IL-18 stimulation is that of T
lymphocytes and NK cells (Hunter et al., 1997). The lower
levels of production of IFN-c in IL-182/2 mice during the
early days of infection might be due to a reduction in the
number of IFN-c-expressing NK cells (Pien et al., 2000),
although the total number of NK cells in IL-182/2 mice was
slightly greater than in wild-type mice (Table 1).
Pneumonia is characterized by the recruitment of phagocytic cells, mainly granulocytes, to the site of infection
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(Skerrett, 1994). The influx of granulocytes into the lung
alveolar compartment at the early phase of influenza virus
infection was markedly increased in IL-182/2 mice
(Table 1). This vigorous recruitment of granulocytes was
associated with proinflammatory stimuli (Greenberger et al.,
1996; Tsai et al., 1998), which might be induced by the heavy
loading of virus infection in the lung (Fig. 2). The enhanced
granulocyte influx into the lung is naturally followed by
excessive production of nitric oxide, which is generated
mostly by granulocytes and is involved in the pathogenesis
of influenza virus-induced pneumonia (Akaike et al., 1996).
No appreciable difference in the local humoral and cellular
immune responses upon influenza virus infection could be
found between IL-182/2 mice and wild-type mice (Table 2).
Even IL-182/2 mice cleared progeny virus from the lung
completely without delay when the specific immune responses were developed effectively. These results indicate that
IL-18 has no effect on the induction and development of
influenza virus-specific immunity but controls the innate
NK cell and IFN system at an early stage of infection.
ACKNOWLEDGEMENTS
This work was supported in part by a grant from the Waksman
Foundation of Japan.
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