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Infection and Immunity, May 1999, p. 2585-2589, Vol. 67, No. 5
Department of Molecular Pathology,
Received 23 December 1998/Returned for modification 19 January
1999/Accepted 1 March 1999
Immunity to mycobacterial infection is closely linked to the
emergence of T cells that secrete cytokines, gamma interferon (IFN- Gamma interferon (IFN- Interleukin-18 (IL-18) is a cytokine that has been identified in the
livers of mice treated with Propionibacterium acnes and lipopolysaccharide (15). This cytokine was originally
identified as an IFN- In order to determine the in vivo functions of IL-18 in
mycobacterial infection, we generated IL-18-deficient mice by gene targeting (23). We used these knockout (KO) mice as a model of systemic infection and showed that IL-18 is important for the development of protective immunity, although these mice infected with
M. tuberculosis did not develop the acute disseminated form of infection.
Mice.
We disrupted the IL-18 gene by homologous
recombination in E14.1 embryonic stem cells, and a targeting vector was
constructed to replace a 3.0-kb fragment of genomic DNA containing
exons 3, 4, and 5 of the IL-18 gene with the neomycin resistance gene
(23). Heterozygous mice were crossed to produce mice
homozygous for the IL-18 gene mutation. IL-18-deficient C57BL/6 mice
were born at the expected Mendelian ratios and were phenotypically
normal and fertile. Their serum IL-18 concentrations, assessed by
enzyme-linked immunosorbent assay (ELISA), were below the detectable
level (the serum IL-18 concentration in normal C57BL/6 mice was
1,000 ± 20 pg/ml), indicating that the IL-18 gene mutation led to
a lack of IL-18 production.
Experimental infections.
The virulent Kurono strain (ATCC
358121) and the avirulent strain Mycobacterium bovis BCG
Pasteur (ATCC 27289) of M. tuberculosis were grown in
Middlebrook 7H9 medium (Difco) to the mid-log phase (21).
The cultured strains were filtered with a 4-µm-pore-size membrane
filter (Millipore) before use so that they were dispersed evenly.
IL-18-deficient and wild-type (WT) mice (10 mice/group) were infected
intravenously (i.v.) via a lateral tail vein with an inoculum of
106 to 107 CFU of Kurono or BCG Pasteur strain
suspended in 100 µl of phosphate-buffered saline (PBS). Mice were
infected by an airborne route by placing them in the exposure chamber
of an airborne infection apparatus (model 099CA4212; Glas-Col, Inc.,
Terre Haute, Ind.). The nebulizer compartment was filled with 5 ml of a
suspension of 105 to 106 CFU of Kurono or BCG
Pasteur strain at a concentration calculated to provide an uptake of
ca. 200 to 500 viable bacilli by the lungs just after inhalation
exposure during exposure for 60 min under the experimental conditions
for this study. The survival of groups of mice for 100 days after
infection with M. tuberculosis or M. bovis BCG Pasteur was recorded, and survival curves were plotted. The lungs from IL-18-KO, WT, and IFN- Histology.
Some mice were sacrificed 50 days after
infection, and some were monitored for up to 100 days postinfection.
Tissue sections (5 µm thick) from paraffin blocks containing lung,
liver, and spleen tissue were stained with hematoxylin and eosin or by
the Ziehl-Neelsen method for acid-fast bacilli. We prepared every lung tissue with white nodular lesions. The sizes of the 10 granulomas were measured with a micrometer (Nikon Optical Co., Tokyo, Japan).
Cytokine assays.
In order to determine whether the splenic
cells of IL-18-KO mice secrete IFN- RT-PCR.
Spleen tissue samples were taken from infected mice
14 or 50 days after infection, frozen in liquid nitrogen, and stored at Macrophage NO assay.
Peritoneal adherent macrophages (5 × 105/well) in RPMI 1640 supplemented with 10% (vol/vol)
fetal calf serum were plated in 96-well culture plates, unstimulated or
stimulated with recombinant IL-18 (100 ng/well; Pepro Tech) or IFN- Reconstitution of IL-18-deficient mice with exogenous IL-18.
Mice were injected subcutaneously with 10 µg of recombinant IL-18
(Pepro Tech) in PBS or PBS alone four times at weekly intervals. The
biological activity of the recombinant IL-18 was evaluated by
determining the 50% effective dose (12 ng/ml) by measuring the
concentration-dependent stimulation of IFN- Statistical methods.
The values were compared by Student's
t test. For all statistical analyses, a P value
of <0.01 was considered significant.
KO and WT littermates were infected i.v. (106 to
107 CFU) or by the airborne route (105 CFU)
with virulent M. tuberculosis Kurono. All the KO and WT mice survived until the date of sacrifice (100 days after infection). When 107 CFU of the Kurono strain was given i.v. to five KO
mice, one mouse died by 86 days postinfection (Fig.
1). Figure
2 shows the CFU in lung tissues of
IL-18-KO, WT, and IFN- When 107 CFU of the Kurono strain was administered i.v. to
KO mice, larger granulomas were observed in their lungs and spleens than in those of the WT controls (Fig.
3A). The average
diameter of all granulomas in the lungs of IL-18-KO mice was
18,620 ± 430 µm, whereas that of WT mice was 5,880 ± 300 µm (P < 0.01). No necrotic lesions were present in
the major organs. Hardly any granulomas were found in the organs of the
WT mice. Similar pathological profiles were observed after infection by
the airborne route, and numerous bacteria were present in the
granulomatous lesions (Fig. 3B).
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Copyright © 1999, American Society for Microbiology. All rights reserved.
Role of Interleukin-18 (IL-18) in Mycobacterial
Infection in IL-18-Gene-Disrupted Mice
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
), interleukin-12 (IL-12), and tumor necrosis factor alpha (TNF-
), resulting in macrophage activation and recruitment
of circulating monocytes to initiate chronic granuloma formation. The cytokine that mediates macrophage activation is IFN-,
and, like IL-12, IL-18 was shown to activate Th1 cells and induce
IFN- production by these cells. In order to investigate the role of IL-18 in mycobacterial infection, IL-18-deficient mice were
infected with Mycobacterium tuberculosis and
Mycobacterium bovis BCG Pasteur, and their capacities to
control bacterial growth, granuloma formation, cytokine secretion, and
NO production were examined. These mice developed marked granulomatous,
but not necrotic, lesions in their lungs and spleens. Compared with the
levels in wild-type mice, the splenic IFN- levels were low but the
IL-12 levels were normal in IL-18-deficient mice. The reduced IFN-
production was not secondary to reduced induction of IL-12
production. The levels of NO production by peritoneal macrophages of
IL-18-deficient and wild-type mice did not differ significantly.
Granulomatous lesion development by IL-18-deficient mice was inhibited
significantly by treatment with exogenous recombinant IL-18. Therefore,
IL-18 is important for the generation of protective immunity to
mycobacteria, and its main function is the induction of IFN- expression.
INTRODUCTION
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
) is
a cytokine secreted by activated T cells and natural killer (NK) cells.
It exerts various immunomodulatory effects on several types of cells
(25) and is one of the major cytokines responsible for
activating macrophages, which mediate nonspecific, cell-mediated,
host defenses (12, 20). IFN- has been shown to be
an important mediator of macrophage activation involved in
controlling a number of intracellular pathogens, including Mycobacterium tuberculosis, Leishmania major,
Leishmania donovani, and Listeria monocytogenes
(2, 10, 14, 18). This protective immunity is closely
associated with emergence kinetics and loss of CD4 T cells that secrete
large amounts of IFN- (17). IFN- has been shown to
play a critical role in protective immunity, as demonstrated by the
severe disseminated form of tuberculosis observed in
IFN--gene-disrupted mice (4, 6). Recently, we also
developed IFN--gene-deficient mice (21, 22) and
demonstrated that endogenous IFN- plays critical roles in
macrophage fusion, cell recruitment, and granuloma assembly
(21).
-inducing factor, which induces IFN-
production by splenocytes, hepatic lymphocytes, and type 1 T helper
(Th1) cell clones (11, 13, 16). IL-18 appears to have
biological functions similar to those of IL-12, which is known to
possess immunoregulatory activities. However, IL-18 was
reported to be strikingly similar to the IL-1 family of cytokines
(1) and showed no similarity to IL-12 (24).
MATERIALS AND METHODS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
-KO mice (five mice each) (21) were retrieved from infected mice 10, 30, and 50 days
after airborne infection, homogenized, diluted, plated on Ogawa slant medium, and incubated at 37°C for 21 days, and the colonies were counted.
, the spleens were harvested from
the IL-18-deficient and WT mice and single cell suspensions were
prepared. The cell suspensions were plated (5 × 105
cells/well) in 96-well culture plates and incubated for 3 days at
37°C in 5% CO2 in air, and the cells were stimulated
with either medium alone or medium containing concanavalin A (ConA, 5 µg/ml), purified protein derivative (10 µg/ml), or live BCG
organisms (103 CFU/well). The concentrations of IL-4,
IL-10, IL-12, IL-1
, IFN-, and tumor necrosis factor alpha
(TNF-) in the culture supernatants of the cells incubated in the
presence of the above reagents were measured by sandwich ELISA
(Biosource International, Calif.).
80°C until required for use, when RNA was extracted as described previously (3). Reverse transcriptase (RT)-PCR was carried out with gene-specific primer sets for inducible NO synthase (iNOS), TNF-, IFN-, IL-12, IL-1, and IL-18 (CLP Inc.) the respective sizes of which were 306, 276, 405, 850, and 447 bp. The size of -actin used as a positive control was 514 bp. The same amounts of
-actin RNA from the spleen tissues used as an internal control were
used in RT-PCR analysis.
(1,000 international units [IU]; Genzyme), and then cultured with the
BCG or Kurono strain overnight. IFN- was added to determine whether
it was able to activate macrophages from the KO mice. The supernatants were collected 36 h after the cultures were seeded and filtered, and the nitrite concentrations were determined by the Griess assay, as
described previously (7).
production by murine
lymph node cells (4 × 105 cells/well) costimulated
with ConA at a suboptimal concentration (750 ng/ml). The lungs
from IL-18-KO mice treated subcutaneously with recombinant IL-18 were
retrieved from the infected mice 7 weeks after airborne infection.
RESULTS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
-KO mice inoculated with 106 CFU
of the Kurono strain by the airborne route. The number of CFU in lung
tissues from IL-18-KO mice was higher than that of WT mice but lower
than that of IFN--KO mice.
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FIG. 1.
Survival curves of mice infected with M. tuberculosis or M. bovis BCG Pasteur. IL-18-KO and
WT mice were infected i.v. with 106 CFU of the Kurono or
BCG Pasteur strain. Data presented are from two separate experiments
with 10 mice in each group.
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FIG. 2.
CFU in lung tissues of IL-18-KO, WT, and IFN- -KO mice
(12 mice each) exposed to 106 CFU of M. tuberculosis by the airborne route. At the indicated days after
infection, four mice from each group were sacrificed and homogenates of
lung tissues were plated. IFN--KO mice were used as positive
controls. Error bars indicate standard errors of the means.
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FIG. 3.
Histologic examination of lung tissues. Mice were killed
7 weeks after infection, and formalin-fixed sections were stained with
hematoxylin and eosin (A, C, D, and E) and for acid-fast bacilli (B).
(A) Tissue from IL-18-KO mice infected with the Kurono strain. A large,
indiscrete granuloma with foamy macrophages is noted. Magnification,
×100. (B) Tissue from IL-18-KO mice infected with the Kurono strain.
Mycobacteria stained red and are recognized in the granuloma by
Ziehl-Neelsen staining. Magnification, ×600. (C) Tissue from WT mice
infected with the Kurono strain. A small, discrete granuloma was
formed. Magnification, ×100. (D) Tissue from IL-18-KO mice infected
with the Kurono strain and treated four times subcutaneously with
recombinant IL-18. The granuloma became smaller. Magnification, ×200.
(E) Tissue from WT mice infected with BCG Pasteur. No granuloma was
recognized. Alveolar septal thickening was noted. Magnification,
×100.
As the defect in the KO mice was genetically defined, the possibility
of recovering immune response function by administering exogenous
recombinant IL-18 was investigated. When IL-18 was given subcutaneously, the sizes of the granulomatous lesions were reduced significantly (mean diameter, 4,820 ± 153 µm), and there were virtually no bacteria in the lesions (Fig. 3C). Significantly less iNOS
and TNF- mRNA was produced by spleen cells of IL-18-KO mice than by
those of untreated KO mice (Fig. 4).
Thus, treatment with exogenous IL-18 reduced the bacterial load
(104 versus 106 CFU), indicating that IL-18
plays an important role in the immune response to M. tuberculosis.
|
In order to examine the major cytokine mRNA expression profiles of
IL-18-KO mice, RT-PCR analysis of the infected spleens was carried out.
No splenic IL-18 mRNA expression was detected in any IL-18-KO mouse
(Fig. 4). IFN-, TNF-, and iNOS mRNA was expressed to a moderate
degree, but the IL-1 and IL-12 mRNA expression levels were somewhat
lower. The IFN-, TNF-, iNOS, IL-1, and IL-12 mRNA
expression levels in the infected mice were significantly lower than
those in the WT mice.
In order to determine whether the absence of IL-18 influenced the
induction and control of other cytokines, the levels of several
cytokines in the culture supernatants of spleen cells were determined
by sandwich ELISA. As shown in Table 1,
spleen cells of KO mice produced significantly less IL-1 than those of WT mice.
|
The NO levels in peritoneal macrophage supernatants were
determined by the Griess assay and referred to a standard
NaNO2 curve. The levels of NO production by unstimulated
peritoneal macrophages from WT and KO mice were low (Fig.
5). When peritoneal macrophages from KO
mice were stimulated overnight with either the BCG Pasteur or Kurono
strain, the NO levels increased to 42 µM (KO mice) and 61 µM (WT
control). When 100 ng of recombinant IL-18 was added to cultures
of macrophages from KO mice, NO production increased to a moderate
degree (57 µM). When 1,000 IU of IFN- was added to macrophages
of KO and WT mice, NO production increased to 64 and 65 µM,
respectively.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
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We have found that large granulomas were induced by inoculation of
an M. tuberculosis strain but that necrotic lesions
were not recognized in major organs. IFN- production by spleen cells from KO mice was reduced moderately, but neither IL-12, TNF-, IL-4,
nor IL-10 secretion by cells of KO and WT mice differed significantly.
Therefore, the expression of Th2 cytokine mRNA, including IL-4 and
IL-10 mRNA, does not contribute to the progress of mycobacterial
infection in this experimental system. The splenic IFN- level in
IL-18-KO mice was significantly lower than that in WT mice,
demonstrating that IL-18 plays an important role in IFN- production.
However, exogenous IFN- and IL-18 were still able to activate the
peritoneal macrophages of IL-18-KO mice to various degrees. The IL-12
levels after mitogenic in vitro challenge of spleen cells from IL-18 KO
and WT mice were almost the same, suggesting that the reduced IFN-
production was not secondary to a low level of induction of IL-12
secretion. Together with the RT-PCR data, these data suggest that Th1
and NK cells of IL-18-KO mice are still able to produce IFN-,
although the NK cell activity and Th1-mediated responses of these
IL-18-deficient mice are compromised (23). It is interesting
that mice devoid of IL-18 production can secrete IFN- to a moderate
degree and exogenous IFN- still can activate macrophages from these
mice. NK cells and NK T cells may secrete IFN- as a compensatory function.
IL-18 has been reported to protect mice against pulmonary and
disseminated infection with Cryptococcus neoformans by
inducing IFN- production (9). When recombinant IL-18 was
administered subcutaneously, the sizes of the granulomas were reduced
significantly (P < 0.01). Therefore, changing the
therapeutic regimens administered to the experimental model mice in our
study may enable mycobacterial infection to be prevented
completely. iNOS and TNF- mRNA produced by spleen cells of IL-18-KO
mice was significantly less than by untreated KO mice. Thus, treatment
with exogenous IL-18 reduced the bacterial load, indicating that
IL-18 plays an important role in the immune response to M. tuberculosis. This finding contrasts with the findings that the
sizes of the granulomatous lesions in IFN--KO and TNF--KO mice
infected with M. tuberculosis were not reduced
significantly by recombinant IFN- or TNF- (8, 21).
IL-18 may play a pivotal role in the immunotherapy of tuberculosis.
It has been reported that IL-18 induces IL-8 and IL-1 via TNF-
production from non-CD14-positive human blood mononuclear cells
(19). In our experiments, IL-18-KO mice expressed far less
IL-1 mRNA than did the WT counterpart. This finding was also
confirmed by ELISA in that the level of IL-1 secretion was lower
than that in WT mice. Further study will be required to explain this
interesting observation.
In summary, we demonstrated that IL-18 influenced the
course of mycobacterial infection in mice. The inflammatory
lesions in IL-18-KO mice were no more severe than those observed
in IFN--KO (4, 6), IL-12-KO (5), and
TNF--KO mice (8). Therefore, IL-18 does not seem to play
a role in Mycobacterium-induced granuloma formation.
Like IL-12-KO mice, IL-18-KO mice displayed reduced IFN- production
in vivo relative to that in WT mice, although secretion of IL-12 by
antigen-challenged spleen cells in vitro was almost normal. These
findings suggest that IL-18 is an important factor involved in IFN-
production in vivo and that IL-18 deficiency cannot be compensated for
by IL-12 and other cytokines.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Molecular Pathology, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, 3-1-24 Matsuyama, Kiyose, Tokyo 204-0022, Japan. Phone: 81 424 92 5075. Fax: 81 424 92 4600. E-mail: sugawara{at}jata.or.jp.
Editor: E. I. Tuomanen
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Infection and Immunity, May 1999, p. 2585-2589, Vol. 67, No. 5
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