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-Deficient Mice by a Concomitant Reduction of TNF-
, IL-12, and IL-18 Production1
,**,
*
First Department of Internal Medicine,
Department of Hygiene,
Second Department of Pathology, School of Medicine, and
§
Department of Molecular Pharmacology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan;
¶
Department of Immunology and Medical Zoology,
||
Laboratory of Host Defenses, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Hyogo, Japan;
#
Laboratory Animal Research Center, Institute of Medical Science,
**
Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; and
Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo, Japan
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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in LPS-induced liver injury following priming with
Propionibacterium acnes. At 1 week after priming BALB/c
mice with P. acnes, a large number of macrophages (M
)
and lymphocytes predominantly infiltrated the portal area, resulting in
the intrahepatic formation of granulomas consisting of epithelioid and
lymphoid cells. In comparison, in IFN- gene-disrupted BALB/c mice
(IFN- knockout mice), the number of infiltrated M was decreased,
with a significant reduction in the number and size of granulomas.
Subsequent elicitation with a low dose of LPS induced massive hepatic
necrosis in wild-type BALB/c mice, with a marked increase in the serum
levels of TNF-
, IL-12, and IL-18 and subsequently of alanine
transferase. In contrast, IFN- knockout mice developed scattered
focal necrosis of the liver with significantly lower levels of serum
alanine transferase as well as drastic decreases in TNF-, IL-12, and
IL-18 production. The administration of an anti-IFN-
neutralizing mAb at the eliciting phase significantly alleviated liver
injury and reduced serum IL-12 and IL-18 levels. Thus, endogenously
produced IFN- is involved in the pathogenesis of this liver injury
model by regulating M infiltration and granuloma formation in the
priming phase as well as cytokine production in the eliciting
phase. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, which is produced mainly by Th1 lymphocytes and NK
cells, is involved in macrophage
(M)3 activation and plays
an important role in M-mediated host reactions. Several lines of
evidence implicate the potential involvement of IFN- in clinical
hepatitis (2, 3, 4). Moreover, enhanced local IFN- production has been
documented to have a role in a number of experimental liver injury
models, including Con A-induced hepatitis,
D-galactosamine-LPS-induced hepatitis, and mouse viral
hepatitis (5, 6, 7).
Liver injury can be also induced by a low dose of LPS in animals primed
with heat-killed bacteria such as Propionibacterium acnes.
This injury occurs in two phases: the early priming and the late
elicitation phases (8). During the priming phase induced by P.
acnes injection, activated mononuclear cells infiltrate the liver
lobules, resulting in granuloma formation consisting mainly of M and
lymphoid cells, whereas massive hepatocellular damage ensues during the
elicitation phase induced by LPS injection (9). Moreover, the
participation of proinflammatory cytokines in liver pathology,
particularly TNF-, has been suggested based on the inhibitory effect
of the administration of neutralizing Ab or antiinflammatory cytokines
(10, 11, 12). In support of this notion, we demonstrated previously that
TNF receptor p55-deficient mice exhibited tremendous reduction in
intrahepatic inflammatory cell infiltration and granuloma formation
during the priming phase and diminished hepatocellular apoptotic and
necrotic changes during the later eliciting phase (13).
The role of IFN- in this model has been investigated using
neutralizing anti-IFN- Abs (14, 15). Because the Abs were
administered in the middle of the priming phase or 24 h before LPS
injection in these studies, the precise role of IFN- in either the
priming or the eliciting phase remains elusive. Moreover, a lack of
pathologic analyses in these studies precluded any definitive
conclusions concerning the effects of IFN- deficiency on granuloma
formation during the priming phase or in the subsequent hepatocyte
apoptotic/necrotic changes after LPS administration. Hence, to clarify
the role of IFN- more definitively, this study explored the
pathologic changes in LPS-challenged, IFN--deficient mice after
priming with P. acnes and their relationship to changes in
the serum levels of IFN--related cytokines.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LPS (Escherichia coli serotype 055.B5) was obtained from Difco Laboratories (Detroit, MI). P. acnes (ATCC 11828, American Type Culture Collection, Manassas, VA) was heat-killed and lyophilized as described previously (12).
Mice
Specific pathogen-free BALB/c mice were obtained from Sankyo
Laboratories (Tokyo, Japan) and thereafter designated as wild-type (wt)
mice. IFN- knockout (gko) mice were generated as described
previously (7) and backcrossed to BALB/c mice for six generations. All
animal procedures in this study complied with the standards set out in
the Guidelines for the Care and Use of Laboratory Animals on the
Takara-machi Campus of Kanazawa University.
Experimental procedures
wt or gko mice that were 8–12 wk of age received an i.v. injection of 1 mg of P. acnes suspended in 100 µl of PBS. After 7 days, the animals were given an i.v. injection of 1 µg of LPS in 100 µl of PBS.
The combined administration of 1 mg of P. acnes and 1 µg of LPS did not induce any lethality until 36 h after LPS challenge in this study. Animals were randomly sacrificed at the indicated timepoints to collect sera and to obtain livers for histologic analyses. Five mice were examined at each timepoint.
In the subsequent experiment, wt mice were i.v. injected with 1 mg of
P. acnes. After 7 days, the animals were injected i.p. with
250 µg of neutralizing anti-mouse IFN- Ab (XMG1.2) (16) or
control rat IgG (ICN Pharmaceuticals, Costa Mesa, CA) at 1
h before LPS injection. Four mice from each group were sacrificed at
6 h after LPS administration to collect sera and to obtain livers
for pathologic analyses.
Histologic and immunohistochemical examination
Liver specimens were fixed with 10% neutral buffered formalin and embedded in paraffin. Deparaffinized thin sections from each paraffin block were stained with hematoxylin and eosin for histologic examinations.
For immunohistochemical analyses, paraffin-embedded liver sections were
dewaxed with Histo-Clear (National Diagnostics, Atlanta, GA) and
dehydrated through graded concentrations of ethanol. After being
treated with microwave Ag retrieval and blocked with avidin, biotin,
and 1% skim milk in PBS, tissue sections were incubated overnight at
4°C with rat anti-mouse M Ab against the M-specific cell
surface protein F4/80 (Serotec, Oxford, U.K.); F4/80 had been diluted
1/2 with 1% skim milk-PBS. The sections were rinsed and subsequently
incubated for 30 min with biotinylated rabbit anti-rat Ig (Dako,
Carpenteria, CA) diluted 1/300 with 1% skim milk-PBS. Tissue sections
were then rinsed and further incubated for 30 min with alkaline
phosphatase (AP)-labeled streptavidin (diluted 1/100 with 1% skim
milk-PBS). The slides were rinsed again in PBS and reacted with AP
substrate solution (Vector Laboratories, Burlingame, CA) containing 1
mM of levamisole for 30 min at room temperature. Finally, sections were
rinsed and counterstained with methyl green.
All slides were evaluated by one of us without prior knowledge of the experimental procedures.
Measurement of granuloma number and size
The numbers and the size of granulomas in the liver from P. acnes-treated mice were histologically determined on 10 randomly chosen microscopic fields at x100 magnification. The area of each granuloma was determined with the help of National Institutes of Health Image Analysis software (version 1.55).
Determination of serum alanine transferase (ALT) and TNF-
Serum ALT levels were determined with a Fuji Dri-Chem 5500V (Fuji Medical System, Tokyo, Japan) according to the manufacturer’s instructions.
Serum murine TNF- levels were measured with an ELISA kit (Quantikine
M, R&D systems, Minneapolis, MN). The detection limit of the assay was
consistently 
20 pg/ml.
ELISA against IL-12
Monoclonal rat anti-mouse IL-12 p70 IgG (clone C15.6) and
another rat anti-mouse IL-12 p70 IgG (clone C17.8) were obtained
from Genzyme (Cambridge, MA); the Ab clone C17.8 was biotinylated.
rIL-12 was also obtained from Genzyme and was used as a standard. Serum
murine IL-12 levels were determined with by ELISA using C15.6,
biotinylated C17.8, and AP-conjugated streptavidin. Enzyme activities
were determined using p-nitrophenylphosphate as a substrate.
The detection limit of the assay was consistently 40 pg/ml.
ELISA against IL-18
IL-18 levels were measured by ELISA using purified rabbit polyclonal Ab against IL-18 (17) and rabbit polyclonal anti-IL-18 conjugated with horseradish peroxidase. 4-amino-antipyrine in potassium phosphate buffer was used as a substrate, and the color intensity was measured at 492 nm. This ELISA detected 0.1–10 ng/ml of IL-18.
Statistical analysis
Data are expressed as mean ± 1 SE. Statistical
significance on the serum ALT level and IL-12 were analyzed by two-way
ANOVA followed by the Scheffe’s multiple comparison procedure. The
numbers and the size of granulomas were analyzed by the Mann-Whitney
U test. The serum ALT, IL-12, and IL-18 levels of
neutralizing IFN- Ab-treated mice were analyzed by the Student
t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In wt mice, serum ALT levels were elevated 
391 ± 92
international units (IU)/L at 7 days after priming with P.
acnes. LPS treatment further increased serum ALT levels nearly
10-fold, reaching a maximum at 12 h and returning to pretreatment
levels by 36 h after LPS challenge (Fig. 1
). In gko mice, priming with P.
acnes induced a slight increase in serum ALT levels (112 ±
28 IU/L). Subsequent LPS challenge further increased serum ALT levels,
which reached one-third of maximal levels of wt mice at 12 h and
returned to almost normal levels by 24 h after LPS challenge in
gko mice (Fig. 1). Although neither wt nor gko mice succumbed until
36 h under these conditions, these results suggest the involvement
of IFN- in the development of this liver injury model.
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To elucidate the basis for the reduced elevation in serum ALT
levels in gko mice, liver tissue was examined histopathologically. No
apparent histologic difference was observed in the livers of untreated
wt and gko mice (Fig. 2, a and
b). At 7 days after P. acnes administration, a
large number of M and lymphocytes infiltrated portal areas, with
additional focal hepatocellular necrosis in wt mice (Fig. 2c). Moreover, in wt mice, granulomas consisted mainly of
epithelioid and lymphoid cells that were diffusely distributed in
hepatic lobules (Fig. 2c), which is consistent with previous
reports (8, 10, 13). At a higher magnification, immunohistochemical
analysis using an anti-M Ab demonstrated the presence of a large
number of M in granulomas (Fig. 2, e and g).
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, was less
evident in livers from P. acnes-primed gko mice (Fig. 2
d) compared with wt mice. Moreover, the number of
granulomas was reduced by nearly 80% in gko mice compared with wt mice
(p < 0.01, Fig. 3A). Furthermore, the area of
each granuloma was decreased by nearly 60% in gko mice in comparison
with wt mice (p < 0.01, Fig. 3B).
Examination at a higher magnification revealed that the main cellular
components of granulomas in gko mice were lymphocytes and neutrophils,
whereas M and epithelioid cells were sparse (Fig. 2f).
This analysis was supported by an immunohistochemical examination,
which detected few M in the granulomas of P. acnes-primed
gko mice (Fig. 2h). Collectively, these results suggest that
IFN- is involved in M infiltration and granuloma formation during
the priming phase.
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At 6 h after LPS challenge, massive cytolytic and coagulative
necrosis and hepatocyte apoptosis were observed in livers from wt mice,
accompanied by a massive infiltration of mononuclear cells, most of
which were lymphocytes (Fig. 4a). Moreover, at the same
time, thrombi were formed in the portal vein, whereas neutrophils and
lymphocytes adhered to hepatic vein endothelium and extravasated
transendothelially as reported previously (12) (Fig. 4a). In
contrast, mononuclear cell infiltration and hepatocyte apoptosis were
less evident in gko mice than wt mice. Moreover, in gko mice, only
focal necrosis was observed, with a scattered infiltration of
lymphocytes, neutrophils, and M (Fig. 4b).
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c), whereas inflammatory reactions disappeared
and necrosis was reduced in gko mice (Fig. 4d).
These results suggest that IFN- plays a role in the establishment
and maintenance of acute hepatic inflammatory reaction and in the
apoptosis/necrosis of hepatocytes even during the elicitation phase in
this model.
Reduction in TNF-, IL-12, and IL-18 (IFN--inducing
factor) production in gko mice
Because TNF-, IL-12, and IL-18 have been presumed to be
involved in this model of acute liver injury (10, 17, 18), the serum
concentrations of these cytokines were measured. In both untreated wt
and gko mice, serum TNF- and IL-18 concentrations were undetectable.
The IL-12 p70 levels of wt and gko mice were 1.34 ± 0.13 ng/ml
and 0.97 ± 0.18 ng/ml, respectively. Priming with P.
acnes induced a slight increase in serum TNF- and IL-12 p70
levels in both wt and gko mice without an increase in serum IL-18
levels in either strain. Subsequent LPS challenge induced a marked
elevation in serum TNF- and IL-12 levels in wt mice, reaching a
maximum within 1 h and 3 h after LPS challenge, respectively,
and declining thereafter (Fig. 5,
A and B). Serum IL-18 levels increased markedly
within 6 h and plateaued until 24 h after LPS challenge in wt
mice (Fig. 5C). Consequently, the elevation in serum levels
of these cytokines preceded the onset of liver injury as represented by
an increase in serum ALT levels. In gko mice, the increase in serum
TNF- levels remained one-hundredth of that in wt mice at 1 h
after LPS challenge and decreased rapidly thereafter to below
detectable levels (Fig. 5A). Moreover, the increase in the
serum IL-12 level of gko mice was slower and less evident compared with
wt mice (Fig. 5B). Furthermore, serum IL-18 remained below
detectable levels during the entire course after LPS challenge (Fig. 5C).
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is presumably required for the up-regulation
of these cytokines and for IL-18 production in particular, and may be
involved in causing acute liver injury.
Effect of administration of a neutralizing IFN- Ab in the
eliciting phase
To clarify the role of IFN- in the eliciting phase, mice were
treated with a neutralizing rat anti-mouse IFN- Ab at 1 h
before LPS injection. At 6 h after LPS administration, the serum
ALT level of anti-IFN- Ab-treated mice (1013 ± 126 IU/L)
was significantly less than that of control Ab-treated mice (1413
± 86 IU/L) (p < 0.05) (Fig. 6A) as reported previously
(14). Furthermore, anti-IFN- Ab-treated mice showed
significantly lower serum IL-12 and IL-18 levels than did control mice
(Fig. 6, B and C). However, no apparent
differences were observed in liver pathology between both groups in
terms of massive cytolytic and coagulative necrosis, hepatocyte
apoptosis, mononuclear cell infiltration, and thrombi in the portal
vein (data not shown). Thus, IFN- may have a limited but important
role in pathologic liver changes during the eliciting phase (induced by
LPS injection) by regulating the production of IL-12 and IL-18.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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exerts pleiotropic effects, including antiviral and
bactericidal activity, activation of M and NK cells, and
up-regulation of MHC class II expression and cell surface Ag such as
ICAM-1 (19, 20). IFN- is produced by NK cells and Th1 cells upon
stimulation with IL-12 and IL-18 (17). Aberrant IFN- production has
been documented in viral hepatitis (2, 3, 4) and experimental liver injury
models (5, 6, 7). Enhanced IFN- is presumed to induce inflammatory
responses and parenchymal toxicity in liver diseases.
Priming with P. acnes renders mice susceptible to subsequent
LPS challenge, leading to extensive liver injury mimicking fulminant
hepatitis (8). This model consists of two phases: the priming phase,
which is induced by P. acnes injection, and the elicitation
phase, which follows LPS administration. Rossol et al. reported that a
neutralizing Ab to IFN- inhibited TNF- production by P.
acnes-primed PBMCs in vitro (21). Moreover, several independent
groups reported that anti-IFN- Abs prevented acute lethality and
hepatic injury with a concomitant reduction in serum TNF- and
IL-1 levels (14, 15). However, because these reports lacked
histologic analysis, the effects of IFN- deletion on liver pathology
remain to be investigated. Thus, to delineate the roles of IFN- in
liver injury more clearly, we analyzed pathologic changes in gko mice
deficient in IFN-; mice were challenged with LPS after priming with
P. acnes.
Priming with P. acnes induced the infiltration of LFA-1- or
Mac-2-positive, activated M (9, 22), leading to intrahepatic
granuloma formation. Granulomas are histologically composed of cells of
the monocyte lineage together with lymphocytes (23). Both Th1-derived
(IL-2/IFN-) and Th2-derived (IL-4/IL-10) cytokines are presumed to
be differentially involved in granuloma formation (23). Mycobacterial
purified protein derivative- and Leishmania donovani-induced
granulomas involve Th1 cytokines, whereas Schistosoma
mansoni egg Ag-derived granulomas involve Th2 cytokines
(24, 25). L. donovani-infected gko mice failed to exhibit
granulomas, implicating IFN- as a key mediator of Th1-dependent
granuloma formation (26). Hence, a reduction in granuloma number and
size in gko mice suggests that the Th1 but not the Th2 response was
mainly responsible for granuloma formation in this model. However, a
substantial number of granulomas were still present in gko mice, in
contrast to the complete absence of granulomas in P.
acnes-primed TNF receptor p55-deficient mice (13). Thus,
IFN--independent TNF- production is also involved in granuloma
formation.
In addition to reduced numbers and sizes of granulomas, the
cellular composition of intrahepatic granulomas in gko mice was
distinct from that seen in wt mice. Granulomas in gko mice consisted
mainly of neutrophils and lymphocytes, with few M. Similar changes
were also observed in gko mice infected with Mycobacterium
tuberculosis or Listeria monocytogenes. These
infections caused granulomatous formations consisting mainly of
granulocytes and devoid of M in gko mice, whereas the granulomas in
wt mice were mainly composed of M (27, 28). Thus, depletion of
IFN- activity caused a failure of M infiltration, and
granulocytes might have compensated for some of the M functions and
contributed to granuloma formation, thereby limiting microbial
invasion.
IL-12, a heterodimer consisting of p35-p40, is produced by M,
dendritic cells, and B cells in response to bacteria and bacterial
products (29). Major activities of IL-12 include the induction of
IFN- production, enhancement of NK activity, and promotion of Th1
cell differentiation (30, 31, 32). Alternatively, IFN- can induce
LPS-induced IL-12 p40 gene activation (33) and IL-12 synthesis in M
in vitro (34, 35). However, the importance of IFN- for IL-12
production in vivo is controversial. Several independent groups claimed
that IFN- was involved in IL-12 production in vivo, in shistosomal
egg Ag infection (25, 36), in tumor rejection (37), in bacillus
Calmette-Guérin infection (38), and in acute viral
hepatitis (39). In contrast, in Toxoplasma gondii infection,
gko mice exhibited levels of IL-12 production that were similar to
those seen wt mice (40), suggesting the possibility of
IFN--independent IL-12 production. In the present model, LPS
challenge after P. acnes priming induced a serum IL-12
elevation even in gko mice, although the magnitude was smaller than in
wt mice. Heinzel et al. also demonstrated that IL-12 production by
splenic M was dependent upon IFN-, and that LPS induced the
generation of similar levels of IL-12 both in gko and wt mice (41).
Thus, IL-12 production may require IFN- differentially, depending
upon the types of cells and stimuli. If splenic M are a major source
of IL-12 even in this model, most IL-12 production may be dependent
upon IFN-. Hence, IFN- deficiency suppressed IL-12 production,
and a small amount of IL-12 may be produced by other cells such as
Kupffer cells. Nevertheless, these results demonstrated that IL-12
production is largely controlled by endogenously produced IFN-, even
in this model.
IL-18, originally called an IFN--inducing factor, is a recently
identified cytokine synthesized by Kupffer cells and activated M
(17). IL-18 in combination with IL-12 induces IFN- production by Th1
and NK cells. M of gko mice, which are allografted with Meth
A tumor cells or administered bacillus
Calmette-Guérin, expressed little IL-18 mRNA, in contrast
to the enhanced expression of IL-18 seen in wt mice (37). However,
IL-18 mRNA is constitutively expressed in the liver (42), and the
processing of IL-18 precursor protein by caspases is required for the
generation and secretion of bioactive IL-18 (43, 44). Hence, the
measurement of secreted IL-18 protein is necessary to evaluate
bioactive IL-18 production. In this model, LPS challenge after P.
acnes priming failed to increase serum IL-18 levels in gko mice.
These results provide the first evidence that IFN- can regulate the
secretion of bioactive IL-18 in vivo, constituting a feedback loop
between these two cytokines.
Diminished liver injury in gko mice, however, cannot exclude the
possibility that attenuated pathologic changes could simply reflect the
reduction in granulomas available for response to subsequent LPS
challenge. Moreover, previous studies using anti-IFN- Abs (14, 15) could not define the role of IFN- during the eliciting phase,
because the Abs were administered during the priming phase or at
24 h before LPS challenge. Hence, to delineate the role of IFN-
during the eliciting phase, we administered a neutralizing
anti-IFN- Ab at 1 h before LPS challenge. Although we
failed to observe a marked attenuation in pathologic liver changes,
serum ALT levels were significantly depressed in
anti-IFN--treated mice compared with control ones. Moreover,
IL-12 and IL-18 production was also decreased significantly by 6 h
after LPS injection. These results suggest that IFN- has a limited
but important role even during the eliciting phase, probably by
inducing the production of several cytokines, such as IL-12 and IL-18.
We demonstrated previously that the TNF receptor p55-mediated signal
was indispensable for granuloma formation during priming, and that TNF
and Fas systems independently govern the process of hepatocellular
apoptotic and necrotic changes at the later phase. Herein, we have
demonstrated that IFN- is also involved in granuloma formation and
in the enhancement of liver injury. Moreover, IFN- deficiency
resulted in an inhibition of elevation in serum IL-12 and IL-18 levels.
These results have provided definitive evidence that the production of
IL-12 and IL-18, which are potent inducers of IFN- production,
requires endogenously produced IFN-, and that these three cytokines
form a feedback loop. Thus, this interaction may thereby aggravate
liver injury. On the basis of these observations, we postulated the
mechanism of LPS-induced liver injury in P. acnes-primed
mice as shown in Fig. 7. Consequently,
breaking down this vicious cycle may eventually prevent the acute
exacerbation of liver injury.
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Acknowledgments |
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Ab, and Drs. Kiyotaka Yamakawa and Shinichi
Nakamura (Kanazawa University, Kanazawa, Japan) for assistance with the
bacterial culture. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Hirokazu Tsuji, First Department of Internal Medicine, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641 Japan. E-mail address:
3 Abbreviations used in this paper: M, macrophage(s); ALT, alanine transferase; wt, wild type; gko, IFN- knockout; AP, alkaline phosphatase.
Received for publication March 30, 1998. Accepted for publication October 2, 1998.
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C. Kalis, M. Gumenscheimer, N. Freudenberg, S. Tchaptchet, G. Fejer, A. Heit, S. Akira, C. Galanos, and M. A. Freudenberg Requirement for TLR9 in the Immunomodulatory Activity of Propionibacterium acnes J. Immunol., April 1, 2005; 174(7): 4295 - 4300. [Abstract] [Full Text] [PDF]
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H. Iizasa, H. Yoneyama, N. Mukaida, Y. Katakoka, M. Naito, N. Yoshida, E. Nakashima, and K. Matsushima Exacerbation of Granuloma Formation in IL-1 Receptor Antagonist-Deficient Mice with Impaired Dendritic Cell Maturation Associated with Th2 Cytokine Production J. Immunol., March 15, 2005; 174(6): 3273 - 3280. [Abstract] [Full Text] [PDF]
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T. Yajima, H. Nishimura, K. Saito, H. Kuwano, and Y. Yoshikai Overexpression of Interleukin-15 Increases Susceptibility to Lipopolysaccharide-Induced Liver Injury in Mice Primed with Mycobacterium bovis Bacillus Calmette-Guerin Infect. Immun., July 1, 2004; 72(7): 3855 - 3862. [Abstract] [Full Text] [PDF]
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 J. Morimoto, M. Inobe, C. Kimura, S. Kon, H. Diao, M. Aoki, T. Miyazaki, D. T. Denhardt, S. Rittling, and T. Uede Osteopontin affects the persistence of {beta}-glucan-induced hepatic granuloma formation and tissue injury through two distinct mechanisms Int. Immunol., March 1, 2004; 16(3): 477 - 488. [Abstract] [Full Text] [PDF]
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Y. Ishida, T. Maegawa, T. Kondo, A. Kimura, Y. Iwakura, S. Nakamura, and N. Mukaida Essential Involvement of IFN-{gamma} in Clostridium difficile Toxin A-Induced Enteritis J. Immunol., March 1, 2004; 172(5): 3018 - 3025. [Abstract] [Full Text] [PDF]
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Y. Ishida, T. Kondo, T. Takayasu, Y. Iwakura, and N. Mukaida The Essential Involvement of Cross-Talk between IFN-{gamma} and TGF-{beta} in the Skin Wound-Healing Process J. Immunol., February 1, 2004; 172(3): 1848 - 1855. [Abstract] [Full Text] [PDF]
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A. Kariyone, T. Tamura, H. Kano, Y. Iwakura, K. Takeda, S. Akira, and K. Takatsu Immunogenicity of Peptide-25 of Ag85B in Th1 development: role of IFN-{gamma} Int. Immunol., October 1, 2003; 15(10): 1183 - 1194. [Abstract] [Full Text] [PDF]
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N. Cuesta, C. A. Salkowski, K. E. Thomas, and S. N. Vogel Regulation of Lipopolysaccharide Sensitivity by IFN Regulatory Factor-2 J. Immunol., June 1, 2003; 170(11): 5739 - 5747. [Abstract] [Full Text] [PDF]
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; n = 5) mice were measured
as described in Materials and Methods. *,
p < 0.05 and **, p <
0.01, compared with untreated animals.
