| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Faculty of Medicine, First Department of Internal Medicine, University of the Ryukyus, Okinawa, Japan;
First Department of Internal Medicine, Kurume University, Kurume, Japan;
R&D Laboratories, Nippon Organon K. K., and
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
production caused by the infection was
significantly attenuated in IL-18KO mice compared with WT mice, as
indicated by reduction in the levels of this cytokine in sera, spleen,
lung, and liver, and its synthesis by spleen cells restimulated with
purified protein derivatives. Serum IL-12p40 level postinfection and
its production by peritoneal exudate cells stimulated with live bacilli
were also significantly lower in IL-18KO mice than WT mice, suggesting
that attenuated production of IFN- was secondary to reduction of
IL-12 synthesis. However, this was not likely the case, because
administration of excess IL-12 did not restore the reduced IFN-
production in IL-18KO mice. In further studies, IL-18 transgenic mice
were more resistant to the infection than control littermate mice, and
serum IFN- level and its production by restimulated spleen cells
were increased in the former mice. Taken together, our results indicate
that IL-18 plays an important role in Th1 response and host defense
against M. tuberculosis infection although the
contribution was not as profound as that of
IL-12p40. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and IL-12 are both
recognized as essential cytokines for eradicating this infection
(4, 5, 6, 7, 8). In contrast, the significance of Th2 cytokines
such as IL-4 and IL-10, which are known to antagonize Th1-mediated
responses (9), has not yet been substantiated because
depletion of these genes did not affect the host protection against
M. tuberculosis (10, 11, 12).
IL-18, originally discovered as an IFN--inducing factor
(13), triggers the production of IFN- by NK and Th1
cells and also promotes the cytolytic activity of NK cells
(13, 14, 15). IL-18 by itself does not initiate Th1 cell
development, but augments this response caused by IL-12
(16). Recently, Hoshino et al. (17) reported
that IL-18 can potentially stimulate the production of Th2 cytokine by
NK and T cells in vitro and its administration in vivo resulted in
higher serum IL-4 and IgE levels (18). Similar findings
were reported by other investigators (19, 20). Thus, IL-18
is currently recognized as a cytokine that can potentially promote both
Th1 and Th2 responses (21), although the precise mechanism
for determining Th phenotypes by this cytokine remains to be
elucidated.
Many investigations have addressed the role of IL-18 in host defense
against a variety of infectious pathogens, including Yersinia
enterocolitica (22), Salmonella
typhimurium (23, 24), Leishmania major
(25, 26, 27), Toxoplasma gondii (28),
Plasmodium berghei (14), and herpes
simplex virus type I (29). In most studies, IL-18 was
demonstrated to protect animals against infection by promoting Th1 type
response. We have reported similar results indicating that endogenous
IL-18 contributed to Th1 response and host resistance to
Cryptococcus neoformans infection (30, 31), and
administration of this cytokine protected mice against fatal infection
(32). Sugawara et al. (33) provided data in
support of the above observations by showing reduced IFN- synthesis
and host resistance to mycobacterial infection in IL-18-deficient mice.
However, the newly identified activity of IL-18 on Th2 responses has
made its role in the host defense to intracellular pathogens
ambiguous.
To critically evaluate the role of IL-18 in immune response and host defense against M. tuberculosis infection, in the present study we compared the role of IL-18 with that of IL-12 in mice lacking the synthesis of either IL-18 or IL-12p40 or both. Furthermore, we examined the effect of overexpression of IL-18 on such responses using mice bearing transgene for mature form of this cytokine. Our results showed a significant contribution of IL-18 to Th1 response and host resistance to this infection, although these effects were less pronounced than those of IL-12p40.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Breeding pairs of IL-12p40 gene-disrupted (knockout
(KO)3) mice on a C57BL/6
background were obtained from The Jackson Laboratory (Bar Harbor, ME).
IL-18KO mice were established as described previously (34)
and back-crossed eight times to C57BL/6 mice. Mice with a deletion of
the genes coding both IL-12p40 and IL-18 (double KO; DKO) were
generated by mating between IL-12p40KO and IL-18KO mice.
IL-18-transgenic (IL-18 Tg) mice in which B and mature T cells could
express mature mouse IL-18 cDNA fused with signal peptide of the mouse
Ig 
-chain under the control of mouse Ig promoter were generated, as
described by Hoshino et al. (35). These mice were bred in
a pathogen-free environment in the Laboratory Animal Center for
Biomedical Science, University of the Ryukyus (Okinawa, Japan). C57BL/6
mice were purchased from Charles River Japan (Osaka, Japan) and used as
a control wild-type (WT) animal for each KO mice. We used hemizygous
IL-18 Tg mice and littermate mice without expression of the transgene
as a control. All mice were used at 8–20 wk of age. All experimental
protocols described in the present study were approved by the Ethics
Review Committee for Animal Experimentation of our university
(University of the Ryukyus, Okinawa, Japan).
Infection of microorganisms
M. tuberculosis H37Rv strain (25618; American Type Culture Collection, Manassas, VA) from the same frozen stock was grown in Middlebrook 7H9 medium (Difco, Detroit, MI) containing 0.05% Tween 80 to mid-log phase. Mice were infected with an i.v. inoculum of M. tuberculosis (1–3 x 105 CFU) suspended in 200 µl normal saline after washing three times with normal saline containing 0.05% Tween 80.
Enumeration of viable M. tuberculosis
Mice were sacrificed 2 and 5 wk after infection, and spleen, lung, and liver were dissected out carefully, 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 nutrient Middlebrook 7H11 agar (Difco) plates, cultured for 2–3 wk, followed by counting the number of colonies.
Preparation of organ homogenates
Mice were sacrificed before and 7, 14, and 35 days after infection; and spleen, lung, and liver were separately homogenized in 2 ml of PBS for spleen and lung or 5 ml for liver by teasing with a stainless mesh. The homogenates were centrifuged, filtered through a 0.22-µm filter (Millipore, Bedford, MA), and kept at -70°C before use.
Culture medium and reagents
RPMI 1640 medium was obtained from Life Technologies (Grand Island, NY), FCS from Cansera (Rexdale, Ontario, Canada), and Con A from Sigma-Aldrich (St. Louis, MO). Purified protein derivatives (PPD) were purchased from Nihon BCG (Tokyo, Japan). Murine rIL-12 was kindly provided by Hoffmann-La Roche (Nutley, NJ).
In vitro stimulation of spleen cells
Spleen cells were prepared from mice on day 14 after infection
with M. tuberculosis and cultured at 2 x
106/ml with various doses of PPD for 48 h.
The culture supernatants were collected and measured for the
concentration of IFN-, IL-4, and IL-13 by ELISA.
Preparation of peritoneal exudate cells and in vitro stimulation with M. tuberculosis
Mice were injected i.p. with 1.5 ml of 3% thioglycolate (Eiken Chemical, Tokyo, Japan), and 4 days later peritoneal exudate cells (PEC) were harvested by two cycles of injection of 5 ml of cold RPMI 1640 supplemented with 10% FCS. The obtained cells were cultured at 2 x 106/ml in the presence or absence of various doses of live M. tuberculosis for 48 h. The culture supernatants were collected and measured for the concentration of IL-12p40 by ELISA.
Measurement of cytokines
The concentrations of IFN-, IL-4, IL-12p40, IL-12p70, and
IL-13 in sera, organ homogenates, and culture supernatants were
measured by specific ELISA kits (purchased from Endogen, Cambridge, MA)
for IFN- and IL-4, from BioSource International (Camarillo, CA) for
IL-12p40 and p70, and from R&D Systems (Minneapolis, MN) for IL-13. The
detection limits of assays for IFN-, IL-4, IL-12p40, IL-12p70, and
IL-13 were 15, 5, 2, 4, and 10 pg/ml, respectively.
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). Survival data were analyzed using the generalized Wilcoxon test. A value of p < 0.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To elucidate the role of IL-18 in host resistance to M.
tuberculosis infection, we compared the susceptibility to this
pathogen among IL-12p40KO, IL-18KO, DKO, and WT mice by examining the
survival of infected mice and the bacterial loads of this pathogen in
the spleen, lung, and liver. As shown in Fig. 1
, neither WT nor IL-18KO mice succumbed
to this infection during the observation periods, while all IL-12p40KO
mice died within 9 wk. Interestingly, the survival time of DKO mice was
significantly shorter than that of IL-12p40KO mice (mean survival time:
60.4 ± 3.6 vs 52.3 ± 6.9 days in IL-12p40KO and DKO mice,
respectively; p < 0.05, by Fisher PLSD test),
suggesting the possible contribution of IL-18 to host protection
because the latter mice produced IL-18 in contrast to the former mice
lacking IL-18 as well as IL-12p40.
|
A). Similar
results were obtained in other organs, although statistical
significance was detected only in the lung between WT and IL-18KO mice
(Fig. 2, B and C). These results indicated some
involvement of IL-18 in host resistance to M. tuberculosis
infection despite the likely smaller contribution than IL-12p40.
|
IL-18 was originally identified as an IFN--inducing factor and
known to profoundly potentiate the production of IFN- by various
cells including NK, NKT, and Th cells (13, 14, 15). Therefore,
we next examined IFN- production in the serum, spleen, lung, and
liver of WT and IL-18KO mice before and 7, 14, and 35 days after
infection with M. tuberculosis. As shown in Fig. 3A–D, IFN- was not
detected or at small levels before infection in the serum and all
organs of these mice. The IFN- levels increased on day 7, reached a
peak level on day 14, and then decreased on day 35 after infection in
WT mice. Similar kinetics were observed in IL-18KO mice, but the levels
in serum, lung, and liver were significantly lower than those in WT
mice at every time point, except for on day 7 in lung. In spleen,
IFN- synthesis tended to be smaller in IL-18KO mice than in WT mice
on days 7 and 14, although the differences were not statistically
significant. These results indicated the significant contribution of
IL-18 to the synthesis of IFN- induced by mycobacterial infection.
In sharp contrast, serum levels of Th2 cytokines including IL-4 and
IL-13 were not much different among these mouse strains at every time
point after infection with M. tuberculosis (data not
shown).
|
-inducing cytokines on the development of Th1 cells during
M. tuberculosis infection by measuring the synthesis of
IFN- by spleen cells from infected mice upon restimulation with PPD.
As shown in Fig. 4, IFN- production by
spleen cells was abrogated in both IL-12p40KO and DKO mice, while a
significant reduction, but not abrogation, was observed in IL-18KO
mice. These results suggested that IL-18 played an important role,
although not essential, in the differentiation of mycobacterial
Ag-specific Th1 cells. In contrast, there was no clear distinction in
Th2 cell development, as indicated by spleen cell production of IL-13
among WT, IL-12p40KO, IL-18KO, and DKO mice, although IL-4 production
was not detected at any doses of PPD (data not shown).
|
in IL-18KO mice
To examine the effect of IL-18 deficiency on IL-12 synthesis, we
compared the serum levels of IL-12p40 and p70 between WT and IL-18KO
mice after infection with M. tuberculosis. As shown in Fig. 5A, IL-12p40 levels were
significantly lower in IL-18KO mice than in WT mice on days 7, 14, and
35 postinfection, although IL-12p70 was under detection limit at every
time point (data not shown). In additional experiments, we examined the
production of IL-12p40 by PEC upon stimulation with live M.
tuberculosis in these mice. Similarly, the in vitro synthesis of
this cytokine was significantly reduced in IL-18KO mice, when compared
with that in WT mice (Fig. 5B). These results suggested that
the attenuated IFN- synthesis in IL-18KO mice may be secondary to
insufficient production of IL-12 rather than lack of IL-18. To confirm
this possibility, we examined the effect of replacement therapy using
rIL-12 on the serum IFN- concentrations in infected IL-18KO mice. As
shown in Fig. 6, the serum levels of
IFN- was strongly reduced in IL-18KO mice, compared with WT mice on
day 14 after mycobacterial infection. The attenuated IFN- level
increased by treatment with rIL-12 in IL-18KO mice, but such increase
was quite partial and did not reach the comparable level to that in WT
mice even when an excess dose of rIL-12 was used. In contrast, the same
treatment completely restored the lacked synthesis of IFN- in
IL-12p40KO mice (data not shown). These results supported the
hypothesis that IL-18 as well as IL-12 contributed to the Th1 response
induced by M. tuberculosis infection.
|
|
To further confirm the role of IL-18 in the protective response
against mycobacterial infection, we examined the effect of IL-18
overproduction on the host defense and Th1 response to this pathogen
using mice expressing the transgene for this cytokine. As shown in
Table I, the number of live bacteria was
significantly reduced in the spleen and in the spleen and lung of IL-18
Tg mice, compared with control mice, on days 14 and 35 after infection,
respectively.
|
, IL-4, and IL-13 in
the two strains of mice. Before infection, all of these cytokines were
detected in the serum of IL-18 Tg, as shown in Fig. 7, but not of control mice. Serum IFN-
was increased at 3-, 7-, and 20-fold higher levels in IL-18 Tg mice
than in control mice on days 7, 14, and 35 after infection with
M. tuberculosis, respectively (Fig. 7A). In
contrast, IL-4 and IL-13 in serum were not much different in these mice
at the same time intervals, except for on day 14 postinfection when
IL-13 production was significantly higher in IL-18 Tg mice (Fig. 7, B and C).
|
, IL-4, and IL-13 by spleen
cells upon restimulation with various amounts of PPD between IL-18 Tg
and control littermate mice on day 14 after infection. As shown in Fig. 8A, IFN- production by
spleen cells restimulated with PPD was significantly higher at each
dose except for 300 ng/ml in IL-18 Tg mice than in control mice.
Interestingly, IL-13 production was significantly increased in IL-18 Tg
mice, when compared with that in control mice (Fig. 8B),
although IL-4 was not detected at any doses of PPD (data not
shown).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
production by Th and NK cells (13, 14, 15) and
potentiated IL-12-induced development of Th1 cells (16).
However, recent studies have reported the involvement of IL-18 in the
induction of Th2 response in the absence of IL-12 production
(17, 18, 19, 20, 21). Such ambiguous effects have made the role of
this cytokine in the host defense against intracellular infectious
pathogens less clear. In the present study, we carefully elucidated the
role of IL-18 in Th1 response and host resistance against M.
tuberculosis infection by using mice lacking or overproducing this
cytokine, and furthermore by comparing the cytokine responses and
clinical course of infection among mice with disrupted genes for
IL-12p40 and/or IL-18. The major findings of our study were: 1)
IL-18-deficiency rendered mice slightly prone to mycobacterial
infection through reduction of IFN- production, but not much
affecting the Th2 response; 2) mice lacking both IL-12p40 and IL-18
were more susceptible to this infection than IL-12p40-deficient mice;
3) IL-18 Tg mice were more resistant to infection through enhancing the
production of IFN-.
Sugawara et al. (33) demonstrated previously no
significant difference in the survival of IL-18KO and WT mice infected
with i.v. administration of M. tuberculosis, but the former
mice had a limited ability in eradicating the airborne infection than
the latter mice, as indicated by the increased number of live bacilli
in lungs. Our present study extended their observations by making
comparative analyses with mice lacking either IL-12p40 or IL-18 or
both. Under IL-18-deficient condition, the survival of mice infected
with i.v.-administered M. tuberculosis was similar to
control mice. However, there was a significant difference in the
survival time between IL-12p40KO and DKO mice: the latter mice
deficient in IL-12p40 and IL-18 synthesis died earlier than the former
mice lacking IL-12p40, but not IL-18. Compatible with these results,
eradication of the pathogen from the spleen and lung was slightly
delayed in IL-18KO mice, when compared with that in WT mice, and the
number of live colonies in the spleen was higher in DKO mice than in
IL-12p40KO mice. Although such a difference was quite small, we would
like to think there is some biological significance, because similar
results were reproducibly obtained in three independent experiments.
Similar findings were recently reported by our laboratory
(31). Elimination of C. neoformans from the
infected site was delayed in IL-18KO mice when compared with that in WT
mice, and DKO mice were more sensitive to this infection than
IL-12p40KO mice. Other investigators also indicated the critical roles
of IL-18 in the host resistance to various infectious pathogens
(22, 23, 24, 25, 26, 27, 28, 29), but there are no studies that have compared its
role with other IFN--inducing cytokines apart from ours.
Recently, IL-23, a novel cytokine which shares IL-12p40 and some
biological activities with IL-12, has been identified
(36). This cytokine induces IFN- production by T cells,
similar to IL-12 and IL-18. Therefore, it should be noted that
IL-12p40KO mice, which were used in the present study to examine the
effect of IL-12-deficient condition, lacked IL-23 as well as IL-12, as
recently indicated by Cooper et al. (37). Thus, our
present data suggested the significant contribution of IL-18, although
much less pronounced than IL-12p40, to the host defense against
mycobacterial infection, similar to cryptococcal infection.
IL-12 is essential for the differentiation of OVA-specific Th1 cells
from naive Th cells, while IL-18 by itself cannot initiate, but
potentiate this response (16). A similar role of IL-18 was
reported during the development of immune responses against infection
with C. neoformans (31). Spleen cells from
IL-18KO mice infected with this fungal microorganism produced smaller
amounts of IFN- upon restimulation with Ags than those from WT mice,
while such production was not detected in IL-12p40KO and DKO mice.
These previous observations are compatible with the present data
showing that Th1 cell development was attenuated in IL-18KO mice and
abrogated in both IL-12p40 and DKO mice during M.
tuberculosis infection. In addition, our data depicting that serum
IFN- levels were reduced in IL-18KO mice and not detected in other
two mice (data not shown) were in concordance with the above scenario.
Taken together, IL-18 was likely to play an unignorable role in the
development of mycobacteria-specific Th1 cells through potentiating,
rather than initiating, such response. In fact, IL-18 Tg mice showed
higher levels of IFN- in sera and showed a higher production of
IFN- by spleen cells upon restimulation with mycobacterial Ags than
control littermate mice.
Serum concentrations of IL-12 were significantly reduced in IL-18KO
mice, compared with WT mice, at every time point after infection with
M. tuberculosis. PEC from IL-18KO mice produced less IL-12
upon in vitro infection with this bacilli than those from WT mice.
Similar results were obtained in IL-12 synthesis by the spleen cells
from infected mice (data not shown). Such attenuated production of
IL-12 under IL-18-deficient condition was also observed by other
investigators (30, 38, 39), although the precise
mechanism remains to be elucidated. These findings implied an
alternative mechanism; the lower level of IFN- synthesis in IL-18KO
mice was due to the reduced production of IL-12, but not due to
deficient IL-18 secretion. In fact, IL-12 provides a much more potent
influence on the induction of Th1 response than IL-18 (16, 31, 34). However, this was not likely the case in our study, because
excess amounts of rIL-12 did not restore the reduced production of
IFN- in the sera of IL-18KO mice with mycobacterial infection. The
same treatment induced serum IFN- production in IL-12p40KO mice to
the comparable level to that in WT mice (data not shown). Thus, IL-18
effects on the Th1 response in mycobacterial infection did not appear
to be merely secondary events of IL-12.
In other alternative mechanisms, expression of IL-12 receptor may be
lowered in T and NK cells from IL-18KO mice, compared with WT mice. To
address this possibility, we compared the responsiveness of cells to
IL-12 by measuring the proliferative response and IFN- production of
spleen cells cultured with or without rIL-12 in the presence of
suboptimal Con A. There was no significant difference in both responses
between IL-18KO and WT mice (data not shown). These results indicated
that the above possibility was not likely to explain the reduced
IFN- synthesis observed in IL-18KO mice, although we have not
directly examined IL-12 receptor expression on these cells.
A new aspect of IL-18 has recently been reported by several
investigators. In contrast to its originally recognized action, they
found IL-18 was potent in inducing Th2 cytokine production in vitro by
NK, T cells, and basophils under particular conditions
(17, 18, 19, 20, 21). In vivo administration of this cytokine resulted
in the progression of Th2 responses including eosinophilic infiltration
and elevation of IgE and IgG1 in serum (18, 19, 20, 21).
Consistent with these findings, IL-18 Tg mice established by
Hoshino et al. (35) spontaneously produced Th2 as well as
Th1 cytokines and developed Th2-type responses with their growth, which
indicated the dual role of this cytokine in determining Th phenotypes.
Interestingly, in our study, IL-18 Tg mice developed predominantly Th1
response, as shown by increased IFN- production, and a high
resistance to M. tuberculosis infection, suggesting that the
committed Th2 response might be shifted toward Th1-dominant condition
during this infection, although IL-13 production was still higher in
these mice. Compatible with this observation, both Th1 response and
host resistance to this microorganism were reduced in IL-18KO mice when
compared with WT mice, while Th2 response did not receive significant
effect in the former mice. Based on these data, IL-18 seems to
contribute primarily to the development of Th1 response rather than Th2
by yet unknown regulatory mechanism during infection with M.
tuberculosis.
In conclusion, the present study addressed more critically the role of
IL-18 in host protective response against M. tuberculosis.
On the basis of data from comparative analyses with gene-disrupted mice
for IL-12p40 and/or IL-18 and experiments using IL-18 Tg mice,
significant contribution of IL-18 to Th1, rather than Th2 response and
host resistance to this infection were established, although these
effects were less pronounced than those of IL-12. Importantly, previous
studies (8) as well as ours depicting the role of IL-12 in
host defense against mycobacterial infection used mice lacking
IL-12p40; and therefore, such studies cannot discriminate the role of
IL-12 from that of IL-23. Interestingly, a recent study by Cooper et
al. (37) have speculated the putative role of this novel
cytokine in host protective responses to mycobacterial infection under
a condition lacking the synthesis of bioactive IL-12. Further
investigations simultaneously using mice deficient of either IL-12p35
or IL-23p19 are necessary to understand the critical role of each
IFN--inducing cytokine in the host defense.
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Kazuyoshi Kawakami, Faculty of Medicine, First Department of Internal Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. E-mail address: kawakami{at}med.u-ryukyu.ac.jp
3 Abbreviations used in this paper: KO, knockout; DKO, double KO; IL-18 Tg, IL-18-transgenic; WT, wild type; PEC, peritoneal exudate cell; PPD, purified protein derivative.
Received for publication October 18, 2001. Accepted for publication April 25, 2002.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
gene-disrupted mice. J. Exp. Med. 178:2243. in resistance to Mycobacterium tuberculosis infection. J. Exp. Med. 178:2249. interferon production in the infected lung but is not required for generation of specific immunity to Mycobacterium tuberculosis infection. Infect. Immun. 68:3322. 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 by NK cells. J. Immunol. 165:941. production. J. Immunol. 159:5528.[Abstract]
This article has been cited by other articles:
|
|
 |
|
  S. Faubel, E. C. Lewis, L. Reznikov, D. Ljubanovic, T. S. Hoke, H. Somerset, D.-J. Oh, L. Lu, C. L. Klein, C. A. Dinarello, et al. Cisplatin-Induced Acute Renal Failure Is Associated with an Increase in the Cytokines Interleukin (IL)-1beta, IL-18, IL-6, and Neutrophil Infiltration in the Kidney J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 8 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Wang, H. Hagberg, C. Mallard, C. Zhu, M. Hedtjarn, C.-F. Tiger, K. Eriksson, A. Rosen, and B. Jacobsson Disruption of Interleukin-18, but Not Interleukin-1, Increases Vulnerability to Preterm Delivery and Fetal Mortality after Intrauterine Inflammation Am. J. Pathol., September 1, 2006; 169(3): 967 - 976. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. W. Wieland, S. Florquin, J. M. Pater, S. Weijer, and T. van der Poll CD4+ Cells Play a Limited Role in Murine Lung Infection with Mycobacterium kansasii Am. J. Respir. Cell Mol. Biol., February 1, 2006; 34(2): 167 - 173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Bafica, C. A. Scanga, C. G. Feng, C. Leifer, A. Cheever, and A. Sher TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis J. Exp. Med., December 19, 2005; 202(12): 1715 - 1724. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Shi, A. Blumenthal, C. M. Hickey, S. Gandotra, D. Levy, and S. Ehrt Expression of Many Immunologically Important Genes in Mycobacterium tuberculosis-Infected Macrophages Is Independent of Both TLR2 and TLR4 but Dependent on IFN-{alpha}{beta} Receptor and STAT1 J. Immunol., September 1, 2005; 175(5): 3318 - 3328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Montero, J. Matilla, E. Gomez-Mampaso, and M. A. Lasuncion Geranylgeraniol Regulates Negatively Caspase-1 Autoprocessing: Implication in the Th1 Response against Mycobacterium tuberculosis J. Immunol., October 15, 2004; 173(8): 4936 - 4944. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Scanga, A. Bafica, C. G. Feng, A. W. Cheever, S. Hieny, and A. Sher MyD88-Deficient Mice Display a Profound Loss in Resistance to Mycobacterium tuberculosis Associated with Partially Impaired Th1 Cytokine and Nitric Oxide Synthase 2 Expression Infect. Immun., April 1, 2004; 72(4): 2400 - 2404. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kaser, S. Kaser, N. C. Kaneider, B. Enrich, C. J. Wiedermann, and H. Tilg Interleukin-18 attracts plasmacytoid dendritic cells (DC2s) and promotes Th1 induction by DC2s through IL-18 receptor expression Blood, January 15, 2004; 103(2): 648 - 655. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Koguchi, K. Kawakami, K. Uezu, K. Fukushima, S. Kon, M. Maeda, A. Nakamoto, I. Owan, M. Kuba, N. Kudeken, et al. High Plasma Osteopontin Level and Its Relationship with Interleukin-12-mediated Type 1 T Helper Cell Response in Tuberculosis Am. J. Respir. Crit. Care Med., May 15, 2003; 167(10): 1355 - 1359. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Gracie, S. E. Robertson, and I. B. McInnes Interleukin-18 J. Leukoc. Biol., February 1, 2003; 73(2): 213 - 224. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME |
; n = 8), IL-18KO (
; n =
8), IL-12p40KO (
; n = 7), and DKO mice (•;
n = 8) were infected with M.
tuberculosis (2 x 105 CFU),
and the number of live mice was noted daily. The experiments were
repeated twice with similar results. *, Values of
p < 0.05, compared with IL-12p40KO mice by the
generalized Wilcoxon test.
) and 35 (
