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*
Department of Immunology, University of Glasgow, Glasgow, United Kingdom; and
Gene Targeting Laboratory, Centre for Genome Research, University of Edinburgh, Edinburgh, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and larger amounts of
IL-4 compared with similarly infected +/- and +/+ mice. In contrast,
when infected with the extracellular Gram-positive bacteria
Staphylococcus aureus, the IL-18-/- mice
developed markedly less septicemia than similarly infected wild-type
(+/+) mice. However, the mutant mice developed significantly more
severe septic arthritis than the control wild-type mice. This was
accompanied by a reduction in the levels of Ag-induced splenic T cell
proliferation, decreased IFN- and TNF-
synthesis, but increased
IL-4 production by the mutant mice compared with the wild-type mice.
These results therefore provide direct evidence that IL-18 is not only
essential for the host defense against intracellular infection, but it
also plays a critical role in regulating the synthesis of inflammatory
cytokines, and therefore could be an important target for therapeutic
intervention. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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3 production by Th1, CD8+, and NK
cells in mice and in humans (1). It shares some of the
biological activities with IL-12, but without significant structural
homology, and serves as a costimulatory factor in the activation of
Th1, but not Th2, cells (2). It appears not to drive Th1
cell development, but synergizes with IL-12 for IFN- production
(3). IL-18 and IL-12 are both produced by activated
macrophages. However, unlike IL-12, IL-18 is also expressed in many
other cell types, including dendritic cells, keratinocytes,
osteoblasts, pituitary gland cells, adrenal cortical cells, intestinal
epithelial cells, skin cells, and brain cells (4, 5, 6, 7, 8, 9, 10).
Recombinant murine IL-18 administration was reported to protect mice
against Crytococcal neuformans and Yersinia
enterocolitica infection (11, 12). To determine the
direct and definitive biological role of IL-18 in vivo, we constructed
a strain of IL-18-/- mice and investigated their
phenotype in response to infections with an intracellular protozoan
parasite, Leishmania major, and an extracellular
Gram-negative strain of bacteria, Staphylococcus aureus. Murine leishmaniasis is the functional prototype of polarized Th1 and Th2 cell responses. Most strains of mice infected with L. major develop an eventually self-healing lesion. The disease progression can be modified and resistance increased by a variety of immunological manipulations (for review, see 13). Disease progression and resistance are associated with the preferential development of Th2 cells or Th1 cells, respectively (for review, see 14). It is generally accepted that in cutaneous leishmaniasis, the preferential induction of IL-12 leads to the expansion of Th1 cells, which activate macrophages to produce large amounts of nitric oxide that mediates the destruction of the parasites in resistant individuals. In contrast, in susceptible patients, the preferential induction of IL-4 leads to the development of Th2 cells secreting IL-4, which inhibits the expression of inducible nitric oxide synthase, thus leading to the unchecked multiplication of the parasites (for reviews, see Refs. 15, 16). We demonstrate here that in contrast to the heterozygous and wild-type mice, which were resistant to L. major infection, the IL-18-/- mice were uniformly susceptible. This was associated with a shift from a Th1 to a Th2 response.
The i.v. injection of mice with an exotoxin-producing strain of S. aureus leads to development of severe septic arthritis (17, 18). The articular lesion exhibits synovial hyperplasia, containing neutrophils, macrophages, and a prominent T cell infiltrate, with associated erosion of underlying cartilage and bone. Anti-CD4 or anti-Vß11 Ab administration to delete superantigen-responsive T cell subsets improves disease outcome following infection (19, 20), confirming a central role of T cell activation in pathogenesis. Moreover, amplification of this T cell response by infection of Vß3 transgenic mice with a strain of toxic shock syndrome toxin-1 (TSST-1)-producing S. aureus led to significantly enhanced disease severity, with systemic involvement and increased mortality (21). This indicates that regulatory pathways normally operate to limit immunologically mediated systemic complications following S. aureus infection. Such pathways include the production of glucocorticoids and anti-inflammatory cytokines. We demonstrate here that mice deficient in IL-18 developed markedly reduced septicemia, but with enhanced septic arthritis. This, again, was accompanied by a shift from the Th1 to the Th2 immune response.
Together these results show directly the critical role of IL-18 in the host resistance against intracellular parasitic infections and in the modulation of inflammatory responses, suggesting that IL-18 may be an important target for therapeutic interventions.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-18 genomic DNA was screened from a 129/sv mouse genomic library (Stratagene, Cambridge, U.K.), subcloned into pBluescript vector (Stratagene, La Jolla, CA), and characterized by restriction enzyme mapping and DNA sequencing. A targeting construct was made to replace exons 4, 5, and 6 with a bacterial ß-galactosidase and neomycin resistance genes as reporter gene and selection marker, respectively. In the targeting construct, the introduced genes and selection marker were flanked by half of exons 3 and 5 for deletion of the start codon of the IL-18 gene. An HSV-tk cassette was introduced at the 5' end of targeting construct. Embryonic stem (ES) cells (E14) were transfected with this linearized targeting vector and selected with G418 and gancyclovir. Double-resistant clones were screened for homologous recombination by Southern blot using a 3' end external probe and confirmed by a 5' end external probe and a neomycin-resistant gene probe. The targeted ES clones were microinjected into the blastocysts of C57BL/6 mice to create chimeras. The chimeric mice were then mated with female CD1 mice to produce heterozygotes, which were then intercrossed as described previously (22) to obtain homozygous, heterozygous, and wild-type littermates for experiments. Mice were screened by Southern blot analysis as described above and by RT-PCR.
RT-PCR
Peritoneal cells were collected from IL-18 homozygous,
heterozygous, or wild-type mice and cultured at 37°C in RPMI medium
in 25-cm2 tissue culture flasks (Costar,
Cambridge, MA) at 1 x 106/ml in the
presence of IFN- (100 U/ml; a gift from Dr. G. Adolf, Bender Wien,
Austria) and LPS (10 ng/ml; Sigma, Poole, U.K.). Cells were collected
16 h after activation, and total RNA was isolated with RNAzol B
(Biogenesis, Poole, U.K.). The mRNA was reverse transcripted with
SuperScript II (Life Technologies/BRL, Paisley, U.K.). PCR was
conducted under standard conditions. Primer pairs were: IL-18: sense,
5'-TTACAGGAGAGGGTAGACATTTTACTATCC-3'; antisense,
5'-CAGCATCAGGACAAAGAAAGCCGCCTCAAA-3'); and ß-actin, sense,
5'-GGGCTATGCTCTCCCTCACGCCATCCTGCG-3'; anti-sense,
5'-TTGGCATAGAGGTCTTTACGGATGTCAACG-3'. The PCR products were
visualized by electrophoresis of 15 µl of the reaction product.
L. major infection in vivo
Groups of homozygous and heterozygous mice (female, 6–8 wk old)
were infected in the right hind footpad with 1 x
106 stationary phase promastigotes of L.
major (LV39). Lesion development was measured at regular intervals
with a constant pressure, spring-loaded, dial caliper (Kroeplin,
Munich, Germany) and was expressed as the footpad thickness increase in
the infected right hind foot compared with that in the uninfected left
hind foot. At the end of experiments, mice were sacrificed, and
footpads were removed. The number of parasites present in the infected
footpad was quantified using a limiting dilution method previously
described (23). Draining lymph nodes and spleens were
harvested at various times during the infection for determination of in
vitro proliferation and cytokine production in response to killed
L. major Ags (23). Cytokines in the culture
supernatant or in the serum were determined by ELISA using paired Ab
(PharMingen, San Diego, CA) as previously described (24).
The lower limit of detection in each assay was as follows: TNF-, 10
pg/ml; IFN-, 30 pg/ml; IL-4, 40 pg/ml; and IL-12 (p40 and p70), 20
pg/ml.
S. aureus infection
S. aureus LS-1 was originally isolated from a swollen joint of a New Zealand Black/White mouse with spontaneous arthritis (a gift from Dr. T. Bremell, University of Lund, Lund, Sweden) (25). This bacterial strain produces large amounts of TSST-1, coagulase, and catalase. The bacteria were kept frozen at -20°C in a PBS solution (0.13 M NaCl, 10 mM sodium phosphate (pH 7.4), 5% BSA, and 10% DMSO) until use. Before use, the bacterial solution was thawed and washed in PBS. Viable counting was used to check the number of bacteria as colony-forming units per milliliter by blood agar plate culture. Groups of male homozygous or wild-type mice were injected i.v. with 1 x 107 live bacteria in PBS. Mice were observed daily for up to 7 days; the number of limbs involved was determined, and footpad/intermalleolar diameters were measured with a dial caliper (Kroeplin). An articular index was derived (three or fewer points per limb): 1, erythema alone; 2, swelling and erythema; and 3, erythema, swelling, and extension/loss of function. The severity of septicemia was judged clinically by characteristic changes (24) in coat appearance, posture, presence of spontaneous movement, and mucocutaneous abscess formation, from which a septic index (severity score; maximum score, 4/mouse) was derived for each animal by two observers in blinded fashion. Viable S. aureus tissue distribution was estimated by whole organ culture as described previously (21). Kidneys and paws were removed and homogenized before dilution in PBS. Blood (100 µl) was also diluted in PBS. Each dilution (50 µl) was plated onto prewarmed blood agar and cultured for 18 h at 37°C to determine the number of CFU present, expressed per milliliter of blood, or per whole organ. Serum was also collected and stored at -70°C until cytokine assay by ELISA. The spleens were removed for determination of proliferation and cytokine production in response to killed S. aureus, TSST-1, or Staphylococcal enterotoxin A (SEA).
Spleen cell proliferation and cytokine production
Splenic single cell suspensions, from L. major-infected or S. aureus-infected mice were cultured at 2 x 106 cells/ml for up to 96 h in RPMI (Life Technologies/BRL, Gaithersburg, MD). The medium was supplemented with 10% FCS, 2 mM L-glutamine, 100 IU/ml penicillin, 100 µg/ml streptomycin (all from Life Technologies/BRL), and 50 µM 2-mercaptoenthanol (Sigma). Cells were stimulated with killed L. major (23) for L. major-infected mice or with killed S. aureus, SEA, or TSST-1 (last two obtained from Sigma) for S. aureus-infected mice (24). Proliferation assays were performed in triplicate in 96-well culture plates (Nunc, Roskilde, Denmark), with addition of 1 µCi of [3H]thymidine (Amersham, Aylesbury, U.K.) in 25 µl during the final 6 h of culture before harvesting onto a glass-fiber filter (Packard, Wallac, Milton Keynes, U.K.) using a Micromate 196 Harvester (Packard). [3H]Thymidine incorporation was measured using a Matrix 96, direct beta counter (Packard). In some experiments duplicate 500-µl cultures were performed for up to 96 h in 48-well plates (Costar, Cambridge, MA), and supernatants were stored at -70°C until estimation of cytokine content by ELISA.
FACS phenotyping
Splenic single cell suspensions were washed in serum-free RPMI, and then 105 cells were incubated with 5 µl of conjugated specific anti-CD3(PE), anti-CD4(FITC), anti-CD8(FITC), anti-ThB (FITC), and anti-Pan NK(FITC) Abs (all from Sigma) or normal IgG control (PharMingen, San Diego, CA) for 20 min at room temperature in the dark and then processed as previously described (24).
Statistical analysis
Statistical analysis was performed using Minitab software
(Minitab, State College, PA). Analysis was performed using log-rank,
2, Mann-Whitney, Student’s
t, or two-tailed log-rank test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The IL-18 gene was disrupted by homologous recombination in E14 ES
cells with a replacement targeting construct (Fig. 1
A). Seven targeted clones
were identified among 278 G418- and gancyclovir-resistant clones by
Southern blot using 3' external probe, and confirmed by 5' external
probe. Southern blot using the neomycin gene as probe demonstrated that
only one copy was hybridized at the expected size in all seven clones
(data not shown). Three targeted ES cell clones were microinjected into
blastocysts; all successfully transmitted the disrupted IL-18 gene
through the germline. A replacement gene allele was carried by
homozygous mutant and heterozygous mice, which was confirmed by
Southern blot using 3' and 5' end external probes (Fig. 1, B
and C). IL-18-/- mice were bred from
one of these clones. They were born at the expected ratio
(+/+:+/-:-/- = 32:59:30). The homozygous IL-18-deficient mice grew
normally and showed no obvious abnormalities up to 40 wk. IL-18 mRNA
was not detectable by RT-PCR in activated macrophages from the mutant
mice, but was strongly present in the cells from control mice (Fig. 1D). Naive IL-18-/- or wild-type
mice have similar percentages of CD4+,
CD8+ T cells, B cells, and NK cell by flow
cytometric analysis (data not shown). Splenic T cells also produced
similar levels of proliferative response and cytokine (IFN- and
IL-4) when activated with Con A (mitogen) or anti-CD3 Ab
(polyclonal T cell activation; data not shown).
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Groups of IL-18-/- mice and heterozygous
littermates were infected with L. major in the right hind
footpad. The lesion was visible at 2 wk after infection and was
indistinguishable in both strains of mice. However, disease development
began to divert from 3 wk after infection. While lesions in the
heterozygous mice were contained, those in the
IL-18-/- mice continued to progress (Fig. 2A). By 40 days, lesions in
the mutant mice began to ulcerate, and the experiments were terminated
as required by the guidelines of animal experimentation of the Home
Office, U.K. At this stage, the parasite loads in the footpads of the
IL-18-/- mice were 2.5
log10 higher than those in the heterozygous mice.
Experiments were repeated twice by comparing the phenotypes of the
mutant and wild-type mice. Again, the IL-18-/-
mice were highly susceptible to L. major infection compared
with the IL-18+/+ mice (Fig. 3A). These results show
directly that IL-18 plays a critical role in host resistance against
the intracellular protozoa parasite, L. major.
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Serum IL-12 and IFN- were measured on day 40 after infection.
Serum from the mutant mice contained markedly higher IL-12 (p40 plus
p70), but significantly less IFN-, than serum from the heterozygous
littermates. IL-4 concentrations for both groups were similar (Fig. 2
B). Spleen cells from both groups of mice proliferated to a
similar level against L. major Ags and had similar
percentages of CD3+, CD4+,
CD8+, CD19+, and NK cells
(data not shown). However, cells from the
IL-18-/- mice produced significantly less
IFN- than cells from the IL-18+/- mice. In
contrast, cells from the mutant mice produced significantly more IL-4
than those from the IL-18+/- mice (Fig. 2C). The lymph node cells from the infected mutant mice also
produced markedly less IFN- and TNF-, but more IL-4 and IL-10,
compared with similarly infected IF-18+/+ mice
following stimulation with killed parasites in vitro (Fig. 3B). Similar results were obtained with spleen cells from
these mice (data not shown).
To determine the kinetics of induction of Th1 response,
IL-18-/- and wild-type mice were infected in
the footpad with 1 x 106 L. major
promastigotes. Mice were sacrificed on days 4, 7, 10, and 14
postinfection, and serum was harvested. Spleen cells were cultured with
killed parasites, and culture supernatants were analyzed for a panel of
cytokines. The wild-type mice had significantly larger spleens than the
infected mutant mice (138 ± 16 vs 83 ± 7 mg;
n = 10; p < 0.05; cumulative data for
mice 4–14 days after infection). Their spleen cells also produced
stronger proliferative responses than those of the mutant mice (Fig. 4A). Spleen cells from the
IL-18-/- mice produced significantly less
IFN- and TNF-, but more IL-4, IL-5, and IL-10, compared with
those from the +/+ mice when cultured with killed parasite (Fig. 4).
IL-12 was not detectable in the culture supernatants. Serum cytokine
levels were generally below detection levels, except for IL-12 which
was comparable in the two groups of mice on day 7 after infection (+/+,
95.22 ± 48.37; -/-, 104.88 ± 48.87 pg/ml). Thus, the
absence of IL-18 predisposes the animals to develop a Th2 phenotype
following immunological activation, as illustrated in vivo by the
prototypic Th1/Th2 polarization model, murine cutaneous
leishmaniasis.
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Within 3 days after i.v. S. aureus infection, all the
wild-type mice showed clinical evidence of septicemia, which progressed
up to 7 days. In contrast, only 28% of the
IL-18-/- mice developed septicemia by day 5
after infection (Fig. 5A).
Interestingly, despite the lower levels of septicemia, the
IL-18-/- mice developed markedly more severe
septic arthritis than the control wild-type mice. Clinical signs of
arthritis were observed within 2 days of infection. After 7 days,
whereas articular inflammation was evident in only 50% of wild-type
mice, up to 75% of IL-18-/- mice developed
arthritis (Fig. 5B). Moreover, the mean arthritic score was
significantly higher in arthritic homozygous mice than in arthritic
control mice from day 2 (Fig. 5C).
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A). By day 7 the levels of
bacteria in the paws and kidneys were comparable in the two strains of
mice. The mutant mice, however, showed lower bacterial count in blood
than the control mice (Fig. 6B).
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We next investigated whether the altered clinical phenotype in the
IL-18-/- mice was reflected in the immune
response following staphylococcal infection. Seven days after
infection, spleen cells from the IL-18-/- mice
displayed significantly lower proliferative responses to TSST-1 (an
exotoxin secreted by the S. aureus LS-1) and SEA than cells
from the control wild-type mice (Fig. 7A). Culture supernatant of
cells from the IL-18-/- mice also produced
markedly lower concentrations of IFN-, but larger amounts of IL-4,
compared with cells from wild-type mice (Fig. 7, B and
C). Interestingly, spleen cells from the infected mutant
mice also produced significantly less TNF- compared with cells from
the control mice when stimulated with the superantigens TSST-1 and SEA
(Fig. 7D).
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and TNF-
than those from the +/+ mice. IL-12 concentrations were comparable in
the two groups of mice (Fig. 8). IL-4 and
IL-10 were below detectable levels. Spleen cells were cultured with
graded numbers of heat-killed bacteria. Cells from the mutant mice
consistently produced less IFN-, TNF-, and IL-6 than those from
the +/+ mice (Fig. 9). IL-4, IL-10, and
IL-12 were not detected in the culture supernatants of both groups
of mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-4 in response to a T cell
mitogen (Con A) or polyclonal activation by anti-CD3 Ab. IL-18,
therefore, enhances Th1 cell differentiation only in the presence of
antigenic stimulation.
It is also of considerable interest that the IL-18-deficient mice
developed significantly less septicemia but more severe septic
arthritis than similarly infected intact mice. This was surprising
because, compared with wild-type mice, the mutant mice developed a
markedly reduced Th1 response, which has been frequently associated
with septic arthritis (20, 28, 29). The reduced septicemia
could well be due to the decreased TNF- synthesis in the
IL-18-/- mice, because this cytokine has been
implicated to have a direct effector role in the pathogenesis of
Gram-positive bacterial shock (30, 31). Our results are
consistent with a recent report showing that IL-18 could up-regulate
TNF- synthesis by human PBMC (32). The mechanism by
which IL-18 influences TNF- synthesis, however, remains to be
addressed. The more severe septic arthritis observed in the
IL-18-/- mice could be due to the higher
initial bacterial loads in the paws compared with those in wild-type
mice. The higher bacterial load in the mutant mice, in turn, could be
the consequence of higher concentration of IL-4 produced by these mice
compared with the intact mice. It has been recently reported that IL-4
and IL-4-dependent Th2 responses promote septic arthritis and
sepsis-related mortality by inhibition of bacterial clearance during
S. aureus infection (33).
In conclusion, we have demonstrated directly the crucial role of IL-18 in host resistance against intracellular L. major infection and in the septicemia and septic arthritis of extracellular Gram-positive S. aureus infection. Furthermore, IL-18 plays a critical role in the in vivo regulation of Th1 and Th2 balance, which frequently determines the outcome of many important infectious and autoimmune diseases. The role of IL-18 in other infections and immunopathology can now be addressed by direct experimentation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. F. Y. Liew, Department of Immunology, University of Glasgow, Glasgow, U.K. G11 6NT. E-mail address:
3 Abbreviations used in this paper: TSST, toxic shock syndrome toxin; ES, embryonic stem; SEA, staphylococcal enterotoxin A.
Received for publication February 17, 1999. Accepted for publication June 28, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production by T cells. Nature 378:88.[Medline]
-inducing factor (IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12. J. Immunol. 158:1541.[Abstract]
production and activates IRAK and NF-
B. Immunity 7:571.[Medline]
-inducing factor) messenger RNA and functional protein by murine keratinocytes. J. Immunol. 159:298.[Abstract]
-inducing factor) is produced by osteoblasts and acts via granulocyte/macrophage colony-stimulating factor and not via interferon- to inhibit osteoclast formation. J. Exp. Med. 185:1005. inducing factor in the adrenal cortex. J. Biol. Chem. 272:2035.-inducing factor ("interleukin-18") in mouse intestinal epithelial cells. Cell Tissue Res. 289:499.[Medline]
production. J. Immunol. 159:5528.[Abstract]
-inducing factor) regulates early cytokine production in, and promotes resolution of, bacterial infection in mice. J. Immunol. 160:299. receptor deficiency on experimental Staphylococcus aureus septicemia and arthritis. J. Immunol. 155:5736.[Abstract]
-inducing factor) induces IL-8 and IL-1ß via TNF production from non-CD14+ human blood mononuclear cells. J. Clin. Invest. 101:711.[Medline]
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