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*
Department of Allergology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; and
Gunma Prefectural College of Health Sciences, Maebashi, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-4, and IL-10 in both
spleen and liver during the early course of the infection. It also
enhanced the mRNA expression of TNF-
, Fas ligand, and
cytokine-inducible nitric oxide synthase. Increased IL-12 p40
production was also observed in the culture supernatant of spleen cells
and in sera of infected mice. In addition, the infection caused massive
liver injury with elevated serum glutamic-oxaloacetic transaminase and
serum glutamic-pyruvic transaminase activities and body weight loss.
Treatment of these infected mice with neutralizing mAb against IL-12
prolonged the survival and diminished the liver injury with reduced
elevation of serum serum glutamic-oxaloacetic transaminase and serum
glutamic-pyruvic transaminase activities and decreased body weight
loss. However, the anti-IL-12 treatment did not affect parasitemia,
and all these mice eventually died. Similar results were obtained when
infected mice were treated with neutralizing mAb against IFN-.
Moreover, anti-IL-12 treatment greatly reduced the secretion and
mRNA expression of IFN- in both spleen and liver. These results
suggest that the lethal P. berghei NK65 infection induces
IL-12 production and that the IL-12 is involved in the pathogenesis of
liver injury via IFN- production rather than the protection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production by NK cells and T cells (1, 2, 3, 4). IL-12 has been
demonstrated to be crucial for the generation of a protective Th1
response against a variety of intracellular pathogens (5, 6, 7, 8, 9) and also
for the pathogenesis of some Th1-associated autoimmune disorders
(10).
An abundance of evidence has been accumulated for the importance of Th
cells in the resolution of blood-stage malarial infection (11, 12, 13, 14).
Protective immunity against the malarial infection with
Plasmodium chabaudi was shown to be mediated by
the activation of Th1 cells, and IFN- was demonstrated to play a
critical role in the control of malarial infection (15, 16, 17).
Plasmodium berghei NK65 is a lethal murine malarial strain,
and P. berghei XAT is its irradiation-induced attenuated
variant (18). Parasitemia in mice infected with blood-stage P.
berghei NK65 increases progressively, and all mice die in 2 to 3
wk, while the P. berghei XAT parasites are spontaneously
cleared in immune competent mice in 3 wk after two peaks of
parasitemia. Moreover, mice recovered from the P. berghei
XAT infection exhibit a strong resistance to the following challenge
with the lethal P. berghei NK65, indicating that P.
berghei XAT is a good model for live vaccine. Therefore,
comparison of immune responses induced by these lethal and attenuated
parasites would lead us to elucidate the mechanisms of protective
immunity and pathogenesis. We previously demonstrated that IFN-
produced by CD4+ T cells plays a pivotal role in the
protective immunity against P. berghei XAT infection (19, 20). We have recently demonstrated that the attenuated P.
berghei XAT infection induces IL-12 production in spleen and that
the IL-12 plays an important role in the protective immunity via
IFN- production (21). However, since anti-IFN- treatment was
demonstrated to prolong the survival of mice infected with the lethal
P. berghei NK65, IFN- was considered to be potentially
involved in the pathogenesis of P. berghei NK65 infection
(19). In the present study, therefore, we asked whether the lethal
P. berghei NK65 also induces IL-12 production and analyzed
the role of IL-12 in the protection or pathogenesis. Here, we show that
the infection induces IL-12 production similar to that of the P.
berghei XAT infection, but on the contrary the IL-12 production is
involved in the pathogenesis of liver injury via IFN- production
rather than the protection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C57BL/6 mice (6–8 wk old) were purchased from Japan SLC (Hamamatsu, Japan). Mice were injected i.v. for malarial infection with a RBC suspension containing 1 x 104 RBC parasitized (PRBC) with a lethal strain, P. berghei NK65 (18). Parasitemia was assessed by the microscopic examination of Giemsa-stained smears of tail blood. The percentage of parasitemia was calculated as follows: parasitemia (%) = [(number of infected erythrocytes)/(total number of erythrocytes counted)] x 100.
RT-PCR analysis
Total RNA was extracted from spleen and liver by using a
guanidine thiocyanate procedure (22). One microgram of total RNA was
reverse transcribed into cDNA using SuperScript RT (Life Technologies,
Gaithersburg, MD) in a reaction mixture of 50 mM Tris-HCl (pH 8.3)
containing 75 mM KCl, 3 mM MgCl2, 0.4 U/µl RNase
inhibitor (Wako Chemicals, Osaka, Japan), 0.2 mM deoxynucleotide
triphosphates, 1 mM DTT, and 0.8 U/µl reverse transcriptase (RT) from
Moloney murine leukemia virus (Life Technologies) after annealing with
oligo(dT) primer (Promega, Madison, WI). The PCR was performed in 10 mM
Tris-HCl (pH 9.0) containing 50 mM KCl, 1.5 mM MgCl2, 0.2
mM deoxynucleotide triphosphates, 0.1% Triton X-100, 0.5 µM each
primer, and 0.025 U/µl Taq DNA polymerase (Toyobo, Osaka,
Japan). Reaction conditions and nucleotide sequences for sense and
antisense primers and internal probes for IFN-, IL-4, IL-10, IL-12
p40 and p35, TNF-, cytokine-inducible nitric oxide synthase (iNOS),
FasL, and hypoxanthine phosphoribosyltransferase were the same as those
described (23, 24, 25, 26, 27). The amplified products were size fractionated by
electrophoresis on a 2% agarose gel, followed by ethidium bromide
staining for UV-assisted visualization and Southern blot hybridization
with 32P-end labeled-internal oligonucleotide probes as
described (28).
Detection of IL-12 p40 and IFN-
Spleen cells were cultured at 6 x 106
cells/ml without addition of parasite Ag in RPMI 1640 medium
supplemented with 10% FCS, 5 x 10-5 M 2-ME and 100
µg/ml kanamycin. Liver mononuclear cells were prepared as described
previously (19) and cultured at 2 x 106 cells/ml
without addition of parasite Ag in the medium. After incubation for
48 h, culture supernatants were harvested and assayed for IL-12
p40 and IFN- in sandwich ELISA using rat anti-mouse IL-12 p40
(C17.8 and C15.6, provided by Dr. G. Trinchieri, Wistar Institute,
Philadelphia, PA) as described (29) and rat anti-mouse IFN-
(R4–6A2 and XMG1.2, PharMingen, San Diego, CA) according to the
manufacturer’s instruction (30), respectively. Murine rIL-12 and
rIFN- were gifts from Dr. M. Kobayashi (Genetics Institute,
Cambridge, MA) and Dr. M. Moriyama (Toray Industries, Kamakura, Japan),
respectively.
Histologic examination
Livers were removed from mice, fixed in 4% paraformaldehyde, embedded in paraffin, and cut into 3-µm sections. Individual sections were examined after staining with hematoxylin and eosin. For the histologic scoring of liver injury, 10 fields that cover the almost whole section were selected, the necrotic-like area in each field was measured at x100 magnification, and the percentage of necrotic-like area was calculated compared with all areas observed. We also measured the necrotic-like cell number and calculated the percentage of necrotic-like cell compared with all cells observed.
Glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) activities
The serum GOT and GPT activities were measured in the Automatic Analyzer 7250 (Hitachi, Tokyo, Japan).
Neutralization of cytokines in vivo with mAbs
To neutralize endogenous IL-12 or IFN-, mice were injected
i.p. with of rat anti-mouse IL-12 p40 (C17.8, IgG2a) or rat
anti-mouse IFN- (XMG1.2, IgG1) (31), 0.3 mg/injection/mouse, for
4 consecutive days from the day of the parasite inoculation and then
twice a week until day 14. These mAbs were purified from ascites on a
protein G column. As a control Ab, normal rat IgG (Sigma, Chemical, St.
Louis, MO) was used.
Statistical analysis
Statistical analysis was performed by Student’s t test, except for survival. Survival was evaluated by generation of Kaplan-Meier plots and log rank analysis. p < 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To examine whether the infection of C57BL/6 mice with a
blood-stage lethal P. berghei NK65 induces IL-12 production,
we first examined mRNA expression of IL-12 and other cytokines in
spleen and liver of infected mice. Mice were inoculated i.v. with
1 x 104 PRBC, spleen and liver were obtained at
various time intervals, and mRNA expression of various cytokines was
examined by RT-PCR (Fig. 1
). IL-12 p40
mRNA expression was increased from as early as 2 days after the
parasite inoculation and peaked on days 4 to 6 in both spleen and
liver. mRNA expression of IFN- and IL-4 was also increased in
similar time kinetics in both spleen and liver, and IL-10 mRNA
expression was also increased, but slightly behind IL-4 mRNA expression
in time kinetics. IL-12 p35 mRNA expression was detected even in spleen
of noninfected mice and was not affected by the infection, while the
expression was hardly detected in liver of noninfected mice and
slightly increased by the infection. mRNA expression of TNF- and
FasL was also increased in both spleen and liver. iNOS mRNA expression
was detected on days 6 to 8 in liver, but slightly in spleen. Thus, the
P. berghei NK65 infection enhanced mRNA expression of IL-12
p40, IFN-, IL-4, IL-10, and TNF-, and also of FasL in spleen and
liver. In contrast to these mRNA expression, iNOS mRNA was detected
slightly in spleen but more in liver in a short time from 6 to 8 days
after the inoculation and became undetectable.
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by spleen cells was analyzed at
a protein level. After i.v. inoculation with PRBC, spleens were
obtained at various time intervals, spontaneous IL-12 p40 and IFN-
production by these cells without addition of parasite Ag in culture
were assayed in ELISA (Fig. 2). IL-12 p40
production was enhanced as early as 2 days after the parasite
inoculation, peaked on day 4, and sharply decreased, while IFN-
production was sharply enhanced on day 4 and gradually decreased. These
results are consistent with those in mRNA expression mentioned above.
Moreover, similar enhancement of IL-12 p40 production was observed in
sera of infected mice (data not shown). These results again suggest
that the P. berghei NK65 infection enhances the production
of IL-12 p40 and IFN-.
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We previously demonstrated that blood-stage P. berghei
NK65 infection causes mononuclear cell infiltration into liver and that
the treatment of infected mice with anti-IFN- prolongs the
survival (19). To examine whether IL-12 produced by the parasite
infection is involved in protection or pathogenesis, infected mice were
treated with neutralizing mAb against IL-12 for 4 consecutive days from
the day of parasite inoculation and then twice a week until day 14.
After i.v. inoculation of mice with PRBC, serum GOT and GPT activities
were elevated, and their body weight was gradually decreased (Fig. 3), with severe anemia. In addition,
massive liver injury with necrotic cells forming focal necrosis-like
lesions and mononuclear cell infiltration were observed by histologic
examination of livers of infected mice compared with that of
noninfected mice (Fig. 4, A
and B). Treatment of infected mice with neutralizing
anti-IL-12 significantly prolonged the survival compared with that
with PBS or control Ab (Fig. 5A). However, the
parasitemia in these mice was not affected by these treatments in level
and time kinetics (Fig. 5B). Similarly,
neutralization of IFN- by injecting its mAb resulted in prolonged
survival (Fig. 5A) as reported previously (19).
Concomitant with the prolonged survival, elevation of serum GOT and GPT
activities and the body weight loss were significantly reduced by the
anti-IL-12 treatment, but not with control Ab (Fig. 3). Similar
reduction of serum GOT and GPT activities was observed when infected
mice were treated with anti-IFN- (data not shown). Moreover, the
liver injury was significantly diminished by treatment with
anti-IL-12, but not with control Ab (Fig. 4). These results suggest
that IL-12 and IFN- are involved in the pathogenesis of liver injury
rather than the protection in the P. berghei NK65
infection.
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production by treatment of infected mice with
neutralizing mAb against IL-12
To further examine whether the pathogenic effect of IL-12 is
mediated by IFN-, we next analyzed the effect of anti-IL-12
treatment on IFN- production in spleen and liver. Spleen cells of
anti-IL-12-treated mice were obtained at various time intervals and
cultured in vitro, and IFN- secreted spontaneously in culture was
assayed. The IFN- production was greatly reduced by the treatment
with anti-IL-12, but not with control Ab (Fig. 6A). IFN- production
by liver mononuclear cells, which were prepared from livers obtained 6
days after the inoculation, was also significantly reduced (Fig. 6B). We then examined the expression of IFN- and
other cytokines at mRNA level in spleen and liver. Consistent with the
above results, RT-PCR analysis revealed that IFN- mRNA expression
was greatly reduced by the treatment with anti-IL-12, but not with
control Ab, in both spleen and liver (data not shown). In contrast, the
expression of IL-4 and IL-10 mRNA appeared not to be greatly affected
by the treatment (data not shown). These results suggest that IFN-
production in spleen and liver of the infected mice is dependent on
IL-12 produced by the infection.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production (21). However, we previously found that IFN-
production might be involved in the pathogenesis of blood-stage lethal
P. berghei NK65 infection (19). In the present study, we
therefore further extended these studies and elucidated that the lethal
P. berghei NK65 infection also induces IL-12 production, but
the IL-12 is involved in the pathogenesis of liver injury via IFN-
production rather than the protection. This is in strong contrast with
our previous results showing the protective effect of IL-12 in P.
berghei XAT infection (21). Thus, IL-12 seems to have both
protective and pathogenic effects depending on the immune responses
elicited by the attenuated and lethal parasites via IFN- production.
The difference between these immune responses, which determines the
outcome of the infection, might be due to the quantity of IL-12
produced, the tissue in which it is produced, the time period during
which its production is sustained, and the presence of other molecules
regulating its production. Further study is currently under
investigation to elucidate more precise mechanisms by which the
attenuated parasite evokes protective immunity and on the contrary the
lethal parasite evokes pathogenesis.
Pathogenic effects of IL-12 have recently been reported (9, 32, 33, 34).
rIL-12 administration induced mononuclear cell infiltration in C57BL/6
mouse liver, occasionally associated with hepatocyte necrosis (32). It
was also demonstrated that low doses of rIL-12 administration into
C57BL/6 mice exhibit anti-viral effect against lymphocytic
choriomeningitis virus infection, whereas high doses of rIL-12
administration are detrimental to the resistance largely mediated by
TNF- and induce necrotic lesions in the spleen (9, 33). Moreover,
IL-12 has recently been demonstrated to be a key cytokine in
Th1-dependent liver injury involving IFN-, which induced by the
injection of Propionibacterium acnes and LPS in sensitive
C57BL/6 mice (34). Thus, these phenomena are highly similar to those
seen in mice infected with the P. berghei NK65, further
suggesting the crucial role of IL-12 in the pathogenesis of liver
injury in the infection.
IFN- and TNF- were reported to be critically involved in causing
liver injury, because active hepatitis was seen in IFN--transgenic
mice (35), Con A-induced hepatitis was suppressed in mice lacking
IFN- (36), and liver injury during endotoxemia was blocked by
anti-TNF- (37). A small amount of rTNF- injection was also
shown to cause a variety of pathologic changes including liver injury
in mice infected with Plasmodium vinckei (38). These results
greatly support the present conclusion that the pathogenic effect of
IL-12 to cause liver injury is mediated by IFN-. Moreover, the
infection enhanced TNF- mRNA expression and neutralization of
TNF- led to the prolonged survival and reduced liver injury (data
not shown). However, anti-IL-12 treatment affected much less or
little mRNA expression of TNF- (data not shown), although the
treatment significantly reduced the mRNA expression and production of
IFN- (Fig. 6
). Further studies are necessary to clarify the
involvement of TNF- in the IL-12-mediated liver injury. In addition,
the P. berghei NK65 infection enhanced the mRNA expression
of iNOS and FasL in both spleen and liver, and the iNOS mRNA expression
was higher in liver than in the spleen of infected mice (Fig. 1). The
latter result may indicate that NO would be involved in the
pathogenesis of liver injury as discussed previously (39). Indeed, iNOS
and FasL have been implicated in the pathogenesis of diseases such as
hypotension, immunosuppression, and cerebral malaria (CM) (40, 41, 42) and
of autoimmune diseases and hepatitis (43, 44, 45), respectively. However,
since liver injury was also observed in the P. berghei
NK65-infected
CBA/Kl-lprcg/lprcg
mice (46), which do not have any functional Fas by point mutation, the
apoptosis induced by Fas-FasL interaction in liver seems not to be
necessary for liver injury in infected mice (T. Yoshimoto et al.,
unpublished data). Further studies are required to elucidate precisely
the mechanism by which to cause the pathogenesis of liver injury by the
infection with P. berghei NK65.
The reason mice die by the infection with P. berghei NK65
remains unknown but could be complicated. In the infection with
P. berghei ANKA (47) and human malaria (48), CM is
considered to be one major cause of mortality, although P.
berghei NK65 has not been reported to cause CM. In the early
course of the infection, IFN- production was induced and peaked at 4
to 6 days after inoculation, which resulted in liver injury and thus in
acceleration of the mortality. This is because that infected mice that
were treated with anti-IL-12 or anti-IFN- showed diminished
liver injury and thus prolonged survival, but these mice eventually
died presumably due to another reason such as severe anemia. As a
matter of fact, preliminary results showed that even infected mice
treated with anti-IL-12 or anti-IFN- appeared to still show
anemia, and thus the anemia seems to correlate with the extent of
parasitemia more than that of liver injury, although further
quantitative measurement of hematocrit is necessary to examine the
effect of these mAb treatment on the extent of anemia.
The experimental CM model induced by blood-stage P. berghei
ANKA infection in mice was demonstrated to be associated with elevated
blood TNF- levels resulting in high production of NO (49). Moreover,
IFN-, IL-3, and granulocyte-macrophage-CSF were reported to be
required for CM development (50, 51, 52). Recently, development of CM has
been demonstrated to be blocked in mice lacking IFN- or TNF- (53, 54). Considering that IFN- is central in the regulation of TNF-
and NO production (53, 54, 55) and that IL-12 has an ability to induce
IFN- and TNF- production (9, 32), IL-12 might play a critical
role in the development of CM in the cytokine cascade as in the
P. berghei NK65 infection.
Taken together, the present results suggest that the infection with
blood-stage lethal P. berghei NK65 induces IL-12 production,
which is critically involved in the pathogenesis of liver injury via
IFN- production rather than in the protection. To our knowledge,
this is the first report on the pathogenic role of endogenous IL-12 in
the parasite infection. Thus, the murine malaria models of lethal
P. berghei NK65 and its attenuated P. berghei XAT
would provide useful and valuable tools for investigation of the
mechanisms by which to develop the protective immunity and cause the
pathogenesis in blood-stage malarial infection.
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Acknowledgments |
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, respectively. We also thank Drs. A. Tsubura
(Kansai Medical University, Osaka, Japan) and H. Maeda (Sankyo, Tokyo,
Japan) for suggestions on histologic analyses for and measurement of
serum GOT and GPT activities, respectively. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Takayuki Yoshimoto, Department of Allergology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
3 Abbreviations used in this paper: L, ligand; PRBC, parasitized RBC; iNOS, cytokine-inducible nitric oxide synthase; GOT, glutamic-oxaloacetic transaminase; GPT, glutamic-pyruvic transaminase; CM, cerebral malaria.
Received for publication August 18, 1997. Accepted for publication January 30, 1998.
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