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Production by NK Cells1
*
First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan;
Laboratory Animal Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan;
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; and
§
Fujisaki Institute, Hayashibara Biochemical Laboratories, Okayama, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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was still detected in these mice at a considerable level
(20–30% of that in control mice). The host resistance was moderately
impaired in IL-12p40-/- mice compared with
IFN--/- mice. Neutralizing
anti-IFN- mAb further increased the lung burdens of organisms.
In addition, treatment with neutralizing anti-IL-18 Ab almost
completely abrogated the production of IFN- and also impaired the
host resistance. Host resistance in
IL-12p40-/-
IL-18-/- mice was more profoundly impaired
than in IL-12p40-/- mice. Administration of
IL-12 as well as IL-18 increased the serum levels of IFN- and
significantly restored the reduced host resistance. Spleen cells
obtained from infected IL-12p40-/- mice did
not produce any IFN- upon restimulation with the same organisms,
while those from infected and IL-12-treated mice produced IFN-. In
contrast, IL-18 did not show such effect. Finally, depletion of NK
cells by anti-asialo GM1 Ab mostly abrogated the residual
production of IFN- in IL-12p40-/- mice.
Our results indicate that IL-18 contributes to host resistance to
cryptococcal infection through the induction of IFN- production by
NK cells, but not through the development of Th1 cells, under the
condition in which IL-12 synthesis is deficient. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell-mediated immunity plays a major role in host defense
(3, 4, 5, 6, 7), and Th1 cytokines, such as IFN-, which acts by
inducing NO-dependent fungicidal activity of macrophages (8, 9), are essential for this response (10). Many
investigators have reported the essential role of IL-12, an important
cytokine for differentiation of Th1 cells (11), in host
resistance to a variety of infectious pathogens (12, 13, 14, 15, 16, 17).
Using mice with a targeted disruption of the gene for IL-12p40 or p35
subunit (IL-12p40-/- or
p35-/- mice), Decken et
al. (17) recently indicated that this cytokine is a
prerequisite for protecting hosts against infection with C.
neoformans. In a series of studies, we have previously
demonstrated that administration of IL-12 promoted the clearance of
fungal organisms from the lung and prevented dissemination to the brain
(18, 19, 20). In contrast, IL-18, a novel cytokine identified
as an IFN--inducing factor (21), is known to potentiate
the differentiation of Th1 cells, although this cytokine by itself
fails to induce this response (22). Several studies showed
that IL-18 plays important roles in host defense against infection with
Yersinia enterocolitica, Salmonella
typhimurium, HSV1 and Leishmania major
(23, 24, 25, 26). We have recently shown that this cytokine plays
an important role in the host resistance against cryptococcal
infection, and its administration protects mice against this infection
(27). Furthermore, IL-18 potentiates the protective
effects of IL-12 against this infection both in in vitro and in vivo
studies (28, 29). However, the contribution of the former
cytokine to host defense against infectious pathogens is not fully
understood because it has been difficult to discriminate the activity
of IL-18 from that of the counterpart cytokine.
In the present study, we elucidated the role of IL-18 in host
resistance to pulmonary and disseminated infections with C.
neoformans using
IL-12p40-/- mice. For
this purpose, we examined the effect of neutralizing anti-IL-18 Ab
on the clinical course of this infection and cytokine responses by
measuring the serum levels of IFN-. Furthermore, we compared the
host resistance of
IL-12p40-/- and
IFN--/- mice or
IL-12p40-/- and
IL-12p40-/-
IL-18-/- mice. Finally,
to define the ability of IL-18 to induce Th1 responses, we tested the
ability of spleen cells obtained from
IL-12p40-/- mice infected
with C. neoformans to produce IFN- upon restimulation
with fungal Ags and the effect of IL-18 treatment on this response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Breeding pairs of
IL-12p40-/- mice on a
C57BL/6 background were obtained from The Jackson Laboratory (Bar
Harbor, ME). IFN--/-
mice were established as described previously (30) and
backcrossed to C57BL/6 mice.
IL-18-/- mice were
established as described previously (31) and backcrossed
to C57BL/6 mice. Mice with a deletion of the genes coding both IL-12p40
and IL-18 were generated by mating between
IL-12p40-/- and
IL-18-/- mice. These mice
were bred in a pathogen-free environment in the Laboratory Animal
Center for Biomedical Science, University of the Ryukyus. C57BL/6 mice
were purchased from SLC Japan (Hamamatsu, Japan) and used as a control
wild-type (WT)4
animal. All mice were used at 8–13 wk of age. All experimental
protocols were approved by the Ethics Review Committee for Animal
Experimentation of our university.
Microorganisms
A serotype A-encapsulated strain of C. neoformans, designated as YC-13, was established from a patient with pulmonary cryptococcosis (32). Infection with this pathogen was self-limited in the lungs of WT mice and did not disseminate to the brain. The yeast cells were cultured on potato dextrose agar plates for 2–3 days before use. To induce pulmonary infection, mice were anesthetized by i.p. injection of 70 mg/kg of pentobarbital (Abbott Laboratories, North Chicago, IL) and restrained on a small board. Live C. neoformans (1 x 106 cells) were inoculated at 50 µl per mouse by insertion of a 25-gauge blunt needle into and parallel to the trachea.
Culture medium and reagents
RPMI 1640 medium was obtained from Life Technologies (Grand Island, NY), and FCS was obtained from Cansera (Rexdale, Ontario, Canada). Con A was purchased from Sigma (St. Louis, MO). Murine rIL-12 was kindly provided by Hoffmann-La Roche (Nutley, NJ). Murine rIL-18 was prepared as described recently by Okamura et al. (21). The above cytokines were i.p. injected at 0.1 and 10 µg per mouse, respectively, everyday for 7 days after infection with C. neoformans.
Enumeration of viable C. neoformans
Mice were sacrificed 3 wk after infection, and lungs and brains were dissected carefully and excised, then separately homogenized in 10 ml of distilled water by teasing with a stainless mesh at room temperature. The homogenates, appropriately diluted with distilled water, were inoculated at 100 µl on potato dextrose agar plates, cultured for 2–3 days, followed by counting the number of colonies.
Measurement of cytokine
Murine IFN- was measured by using ELISA kit (Endogen,
Cambridge, MA). The sensitivity of the assay was 15 pg/ml.
Antibodies
Anti-IFN- mAb (rat IgG) was purified by a protein G column
kit (Kirkegaard & Perry Laboratories, Gaithersburg, MD) from
ascitic fluid obtained from nude mice injected i.p. with a hybridoma
(clone R4-6A2, purchased from American Type Culture Collection,
Manassas, VA). To block endogenously synthesized IFN-, mice were
injected i.p. with this mAb at 200 µg on day -1, 0, +3, +7, and +14
of infection. Rat IgG (ICN Pharmaceuticals, Auora, OH), was used as a
control Ab.
Neutralizing anti-IL-18 Ab was prepared from sera of rabbits
immunized with murine rIL-18. A dose of 200 µg of anti-IL-18 Ab
completely blocked IFN--inducing activity of 50 ng IL-18 in spleen
cells stimulated with Con A. To neutralize endogenously produced IL-18,
mice were injected i.p. with the Ab at 400 µg on day -1, 0, +3, +7,
and +14 of infection. Rabbit IgG (Wako Pure Chemical Industries, Osaka,
Japan) was used as a control Ab.
Anti-
TCR mAb (hamster IgG) was purified by using a protein G
column kit from serum-free culture supernatants of a hybridoma (clone
UC7-13D5, purchased from American Type Culture Collection). Anti-asialo
GM1 (ASGM1) polyclonal Ab was purchased from Wako Pure Chemical
Industries. To deplete T or NK cells, mice were injected i.p.
with anti- TCR or -ASGM1 Ab at 200 µg on day -3, 0, +3,
and +7 of infection. Hamster IgG (Organon Teknika, Durham, NC) and
rabbit IgG were used as the control Ab. Flow cytometry was performed as
described previously by our laboratory (33) using lung
intraparenchymal leukocytes obtained from infected
IL-12p40-/- mice. When
lymphocyte population was gated on forward and side scatter profiles,
the results showed 3.7% TCR-bearing T cells and 18.2%
ASGM1+ cells. We confirmed that treatment with
each Ab almost completely depleted the corresponding cell population.
Thus, only 0.3% TCR-bearing T cells were present after
treatment with anti- TCR mAb and 0.7%
ASGM1+ cells after treatment with
anti-ASGM1 Ab.
In vitro stimulation of spleen cells
Spleen cells were prepared from mice 2 wk after infection with
C. neoformans and cultured at 2 x
106/ml with various doses of viable organisms or
1 µg/ml of Con A for 48 h. The culture supernatants were
collected and measured for the concentration of IFN- by ELISA.
Statistical analysis
Analysis of data was conducted using Statview II software (Abacus Concept, Berkeley, CA) on a Macintosh computer. Data are expressed as mean ± SD. Statistical analysis between groups was performed using the ANOVA test with a post-hoc analysis (Fisher PLSD test). A value of p < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the first step, we examined the role of endogenously
synthesized IL-12 in host resistance against cryptococcal infection by
intratracheally infecting
IL-12p40-/- and WT mice
with C. neoformans, and the number of viable organisms in
lungs and brains were compared between these mice. None of the infected
mice died during the observation period (data not shown). As shown in
Fig. 1
A, the lung burdens of
this fungal pathogen were significantly higher in
IL-12p40-/- mice than in
WT mice at 3 wk after infection. C. neoformans did not
disseminate to the brain in all nine WT mice, while a considerable
number of organisms was detected in the brain of five of seven
IL-12p40-/- mice (Fig. 1B). Thus, in
IL-12p40-/- mice, both
lung clearance of C. neoformans and prevention of
dissemination of infection to the brain were apparently impaired,
compared with the WT mice.
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in host resistance to C.
neoformans in IL-12p40-/- mice
In WT mice, IFN- was detected in serum at day 3 after
infection, reached to a maximal level at days 7 and 14, and then
decreased. In IL-12p40-/-
mice, IFN- production was markedly reduced, but still detected at a
considerable level, 20–30% of that in WT mice (data not shown). In
the next experiment, therefore, we examined the contribution of
residual IFN- in host defense under IL-12-deficient condition by
examining the effect of neutralizing anti-IFN- mAb on the lung
burdens of C. neoformans in
IL-12p40-/- mice. As
shown in Fig. 2, the number of viable
organisms in lung significantly increased by neutralizing endogenously
synthesized IFN- compared with IgG-treated control mice, and
the increase was almost comparable to the levels detected in
IFN--/- mice. These
results suggested that the residual IFN- was still functional in
eliminating the pathogen from the lungs in
IL-12p40-/-
mice.
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To define the role of IL-18 in host defense under IL-12-deficient
conditions, we elucidated the effect of neutralizing anti-IL-18 Ab
on the fungal burdens in lungs of
IL-12p40-/- mice at 3 wk
after infection with C. neoformans. As shown in Fig. 3A, the number of viable
pathogens in the lungs was significantly higher in
IL-12p40-/- mice than in
WT mice, and treatment with anti-IL-18 Ab significantly increased
the lung burden, whereas control rabbit IgG did not show such effect.
The lung clearance of C. neoformans was worse in mice with
disruption of both IL-12p40 and IL-18 genes than in
IL-12p40-/- mice. The
magnitude of impaired host resistance in the former group was almost
comparable to that in
IFN--/- mice. The host
resistance in IL-18-/-
was less impaired than in
IL-12p40-/- mice (Fig. 3B).
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in these
mice at 14 days after infection. As shown in Fig. 4A, treatment with
anti-IL-18 Ab almost completely abrogated the synthesis of IFN-
in IL-12p40-/- mice.
Serum levels of IFN- were hardly detected in
IL-12p40-/-
IL-18-/- mice, while
considerable levels of IFN- were detected in
IL-12p40-/- and
IL-18-/- mice (Fig. 4B).
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We further examined the effect of exogenous administration of
IL-18 on lung burdens of C. neoformans in
IL-12p40-/- mice to
confirm the protective effect of this cytokine under IL-12-deficient
conditions. For this purpose,
IL-12p40-/- mice infected
with C. neoformans were treated daily with i.p. injections
of IL-18 or IL-12, as a control, during the first 7 days, and the
number of viable organisms in the lungs was examined at 3 wk after
infection. As shown in Fig. 5A, treatment with IL-18
lowered the lung burdens by almost 10-fold, although the magnitude of
this effect was less than that of IL-12 treatment, which was 100-fold
different compared with untreated mice. In addition, serum levels of
IFN- were measured in these mice at 14 days after infection. As
shown in Fig. 5B, IL-12 as well as IL-18 increased the serum
concentrations of IFN- in
IL-12p40-/- mice,
although the effect was larger in the former cytokine than in the
latter.
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To define the mechanism of the protective effect of IL-18, we
examined the effects of IL-18 on the differentiation of Th1 cells in
IL-12p40-/- mice infected
with C. neoformans. For this purpose, spleen cells were
obtained from these mice at 14 days after infection and restimulated
with the same organisms, followed by measurement of the concentration
of IFN- in the culture supernatants. As shown in Fig. 6A, spleen cells obtained from
IL-12p40-/- mice did not
produce any detectable amount of IFN- upon stimulation with C.
neoformans, while they synthesized a large amount of IFN- by
Con A stimulation (see Fig. 6). In contrast, spleen cells derived from
infected WT mice produced a considerable amount of IFN- upon
stimulation with C. neoformans. These results suggested that
endogenously synthesized IL-18 alone did not induce differentiation of
Th1 cells.
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production upon stimulation with C.
neoformans or Con A. As shown in Fig. 6
B, spleen cells
derived from both infected/PBS-treated and infected/IL-18-treated mice
did not produce any detectable amount of IFN- upon stimulation with
the fungus, but induced its synthesis at large amounts by Con A
stimulation (see Fig. 6). In contrast, IL-12 treatment induced a
considerable production of IFN- by spleen cells restimulated with
C. neoformans.
Contribution of NK cells to production of IFN- in
IL-12p40-/- mice
Finally, to determine the cellular source of IFN- under
IL-12-deficient conditions, we examined the effect of depletion of
innate immune cells on serum levels of IFN- in infected
IL-12p40-/- mice. For
this purpose, IL-12p40-/-
mice, which received either anti-ASGM1 Ab or anti- TCR
mAb, were infected with C. neoformans and serum levels of
IFN- were measured at 2 wk after infection. As shown in Fig. 7, A and B,
depletion of NK cells markedly reduced serum levels of IFN-, while
treatment with anti- TCR mAb showed only a marginal effect.
These results indicated that NK cell was the major source of IFN-
production in response to IL-18 after infection with C.
neoformans under conditions of defective IL-12.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production by innate immune cells
(34, 35, 36) and development of Th1 cells (11).
Using mice with a disrupted gene of IL-12p35 or p40, Decken et al.
(17) recently demonstrated that IL-12 was essential for
the production of IFN- and host resistance to infection with
C. neoformans. They also demonstrated that in both
IL-12p35-/- and
p40-/- mice, the survival
time was shorter after infection and the lung burdens of organisms
significantly increased compared with the respective values in WT mice.
The production of IFN- by spleen cells derived from these mice
infected with C. neoformans was mostly abrogated compared
with WT mice. In the present study using
IL-12p40-/- mice, similar
results were obtained with regard to the lung burdens of C.
neoformans. Although the above investigators did not examine the
effect of disruption of the IL-12 gene on the dissemination of
infection from the lung to brain, we demonstrated here that brain
dissemination was enhanced in these mice.
Our results showed that IFN- synthesis was profoundly impaired in
IL-12p40-/- mice after
infection with C. neoformans, as indicated by the low serum
levels of this cytokine. Interestingly, however, a considerable level
of IFN- (20–30% of that in WT mice) was detected in the serum of
IL-12p40-/--infected
mice. Our data were consistent with those by Magram et al.
(37), who demonstrated that
IL-12p40-/- mice did not
fail completely to produce IFN- following endotoxin administration
and secreted IFN- by immune lymph node cells upon stimulation with
specific Ags. Furthermore, in
IL-12p40-/- mice, the
fungal organisms did not grow over the initial load following infection
of the lungs, which indicated the existence of IL-12-independent
mechanisms for eradicating these pathogens. In agreement with this
argument, the magnitude of impairment of host resistance was not
markedly severe in
IL-12p40-/- mice compared
with IFN--/- mice, and
the lung clearance of C. neoformans in the former group was
further impaired by neutralization of endogenously synthesized IFN-
to levels comparable to those in the latter mice. Considered together,
these results demonstrated that the residual IFN- was still
functional in the host resistance to cryptococcal infection and
suggested the involvement of IL-18 in the production of IFN- in
IL-12p40-/-
mice.
Although IL-12 has been recently evaluated as an essential cytokine in
host resistance to a variety of organisms including C.
neoformans (12, 13, 14, 15, 16, 17), the contribution of IL-18
remains to be fully elucidated. In our previous study, we showed that
IL-18 exerted a protective activity against lethal infection with
C. neoformans and was involved in the host resistance to a
weakly virulent strain of this fungal pathogen (27). The
latter finding was evident in the results of experiments that examined
the effect of neutralizing anti-IL-18 Ab on the local host defense
in the lungs. Similarly, several investigators have recently reported
the important role of this cytokine in host defense against infection
using neutralizing Ab or
IL-18-/- mice
(23, 24, 25, 26). However, the possible influence of the
compensatory effects of IL-12 has not been excluded, and the main
contribution of the two IFN--inducing cytokines remains to be
elucidated. In the present study, we extended these findings by
defining the role of IL-18 in host resistance to cryptococcal infection
without any influence of endogenously synthesized IL-12. Neutralization
of IL-18 almost completely abrogated the production of IFN- and
further impaired the lung clearance of this pathogen in
IL-12p40-/- mice. In
comparison, both IFN- synthesis and host defense were further
impaired in mice with dual disruption of the genes of IL-12p40 and
IL-18 compared with
IL-12p40-/- mice.
Furthermore, comparative analysis between
IL-12p40-/- and
IL-18-/- mice suggested
the predominant contribution of IL-12 over IL-18. Thus, our results
clearly demonstrated that not only IL-12 but also IL-18 played
important role in the host resistance against infectious pathogen.
IL-18 is known to induce the synthesis of IFN- by NK and Th1 cells
and by B cells and macrophages in collaboration with IL-12 (21, 28, 38, 39, 40, 41). Importantly, IL-12 and IL-18 activate NK and Th1
cells to produce IFN- in a synergistic manner. Robinson et al.
(22) demonstrated that IL-18 by itself did not induce the
differentiation of Th1 cells from naive T cells, but potentiated
IL-12-induced Th1 cell development. Similar results were recently
reported by Stoll and coworkers (42). However, whether
IL-18 alone induces the development of Th1 cells in vivo remains to be
determined. In agreement with these findings, in the present study, Th1
cells did not develop after infection with C. neoformans in
IL-12p40-/- mice in which
a considerable production of IL-18 was observed although it was
significantly reduced compared with the WT mice (data not shown).
Furthermore, administration of IL-18 did not induce the differentiation
of Th1 cells in infected
IL-12p40-/- mice, while
Th1 response was evident by treatment with IL-12. These results
indicated that IL-18 protected mice against infection with C.
neoformans not through the induction of development of Th1 cells,
but by potentiating IL-12-induced Th1 cell development under normal
conditions.
Our results also demonstrated that the residual synthesis of IFN- in
IL-12p40-/- mice was
almost completely abrogated by depleting innate immune cells,
especially NK cells. These cells are known to produce large amounts of
IFN- upon stimulation with IL-18 (28, 40, 41) and to
play an important role in early host resistance against infection until
the development of acquired immunity (43, 44, 45). Recently,
we indicated that NK cells were involved both in vitro and in vivo in
the elimination of C. neoformans through the production of
IFN- after administration of IL-12 and IL-18 (28, 29).
Considered collectively, these findings suggested that the protective
effect of IL-18 against cryptococcal infection was mediated by
activating NK cells to produce IFN- in IL-12-deficient
mice.
In conclusion, we demonstrated in the present study that IL-18 is a potent cytokine that by itself contributes significantly to the host resistance against infection with C. neoformans, although the involvement of IL-12 appears to be more important than that of IL-18 in our comparative analysis in IL-12p40-/- and IL-18-/- mice. These results suggest that IL-12 as well as IL-18 can be the target cytokines for the development of immunomodulating therapy against intractable cryptococcal infection, particularly in severely immunocompromised patients.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Kazuyoshi Kawakami, First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan.
3 Current address: Division of Infectious Diseases, Department of Internal Medicine, University of Kentucky, Lexington, KY 40536.
4 Abbreviations used in this paper: WT, wild type; ASGM1, asialo GM1.
Received for publication September 28, 1999. Accepted for publication May 4, 2000.
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References |
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|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
synthesis and resistance during acute infection with Toxoplasma gondii. J. Immunol. 153:2533.[Abstract]
production by T cells. Nature 378:88.[Medline]
production and activates IRAK and NF
B. Immunity. 7:571.[Medline]
-inducing factor) regulates early cytokine production in, and promotes resolution of, bacterial infection in mice. J. Immunol. 160:299. interferon production in mice infected with virulent Salmonella typhimurium. Infect. Immun. 67:478. production. J. Immunol. 159:5528.[Abstract]
by natural killer cells. Infect. Immun. 65:3594.[Abstract]
-/-, but not in TNF-
-/- mice: role for IFN- in activating apoptosis of hepatocytes. J. Immunol. 159:1418.[Abstract]
interferon by natural killer cells from Toxiplasma gondii-infected SCID mice: regulation by interleukin-10, interleukin-12, and tumor necrosis factor . Infect. Immun. 62:2818. T cells for production of IFN- is mediated by bacteria via macrophage-derived cytokines IL-1 and IL-12. J. Immunol. 154:5832.[Abstract]
production and type 1 cytokine responses. Immunity 4:471.[Medline]
production from activated B cells. Proc. Natl. Acad. Sci. USA 94:3948. upon combined stimulation with interleukin (IL)-12 and IL-18: a novel pathway of autocrine macrophage activation. J. Exp. Med. 187:2103. interferon production by natural killer cells is important in defense against murine listeriosis. Infect. Immun. 59:2892. that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. J. Exp. Med. 178:567.This article has been cited by other articles:
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 C. Biondo, A. Midiri, M. Gambuzza, E. Gerace, M. Falduto, R. Galbo, A. Bellantoni, C. Beninati, G. Teti, T. Leanderson, et al. IFN-{alpha}/{beta} Signaling Is Required for Polarization of Cytokine Responses toward a Protective Type 1 Pattern during Experimental Cryptococcosis J. Immunol., July 1, 2008; 181(1): 566 - 573. [Abstract] [Full Text] [PDF]
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 G.-H. Chen, M. A. Olszewski, R. A. McDonald, J. C. Wells, R. Paine III, G. B. Huffnagle, and G. B. Toews Role of Granulocyte Macrophage Colony-Stimulating Factor in Host Defense Against Pulmonary Cryptococcus neoformans Infection during Murine Allergic Bronchopulmonary Mycosis Am. J. Pathol., March 1, 2007; 170(3): 1028 - 1040. [Abstract] [Full Text] [PDF]
|
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 E. Mavoungou Interactions between natural killer cells, cortisol and prolactin in malaria during pregnancy. Clin. Med. Res., March 1, 2006; 4(1): 33 - 41. [Abstract] [Full Text] [PDF]
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|
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K. Uezu, K. Kawakami, K. Miyagi, Y. Kinjo, T. Kinjo, H. Ishikawa, and A. Saito Accumulation of {gamma}{delta} T Cells in the Lungs and Their Regulatory Roles in Th1 Response and Host Defense against Pulmonary Infection with Cryptococcus neoformans J. Immunol., June 15, 2004; 172(12): 7629 - 7634. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Blackstock and J. W. Murphy Role of Interleukin-4 in Resistance to Cryptococcus neoformans Infection Am. J. Respir. Cell Mol. Biol., January 1, 2004; 30(1): 109 - 117. [Abstract] [Full Text] [PDF]
|
|
|
|
|
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C. Biondo, C. Beninati, M. Bombaci, L. Messina, G. Mancuso, A. Midiri, R. Galbo, and G. Teti Induction of T Helper Type 1 Responses by a Polysaccharide Deacetylase from Cryptococcus neoformans Infect. Immun., September 1, 2003; 71(9): 5412 - 5417. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Fieschi, S. Dupuis, E. Catherinot, J. Feinberg, J. Bustamante, A. Breiman, F. Altare, R. Baretto, F. Le Deist, S. Kayal, et al. Low Penetrance, Broad Resistance, and Favorable Outcome of Interleukin 12 Receptor {beta}1 Deficiency: Medical and Immunological Implications J. Exp. Med., February 17, 2003; 197(4): 527 - 535. [Abstract] [Full Text] [PDF]
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