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in Mice Lacking IFN Regulatory Factor-1
*
Amgen Inc., Thousand Oaks, CA 91320; and
Amgen Research Institute, Toronto, Ontario, Canada
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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were studied in mice lacking IFN
regulatory factor-1 (IRF-1). IRF-1 knockout (KO) mice showed no
mortality after the injection of a dose of LPS lethal in intact control
mice (LD95). KO mice showed lower circulating levels of TNF
and IFN- than controls. KO mice also showed lower TNF and IFN-
mRNA in the spleen or liver than controls. KO mice had smaller spleens
than controls, which contained similar percentage but lower absolute
count of macrophages and lower percentage and absolute count of NK
cells. IRF-1 KO mice survived longer than controls after the
coinjection of LPS and galactosamine. IRF-1 KO mice also showed less
mortality than controls after the injection of Con A and in a model of
cerebral malaria. After the injection of a lethal dose of TNF
(LD88), mortality was similar between KO and intact mice.
Mortality was also similar after the coinjection of two nonlethal doses
of TNF and IFN-, a lethal combination (LD100). This
study shows that the lack of IRF-1 protects against the mortality
associated with disease models mediated by TNF and IFN- but has no
effect on the mortality directly induced by TNF and IFN-. The lack
of IRF-1 appears to result in impaired production of TNF and IFN-,
reflecting a down-regulation of gene expression in the liver and spleen
as well as a reduction in the number of splenic
cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß,
contributing to the first reaction to viral invasion
(1, 2, 3, 4); of inducible NO synthase, allowing the production
of NO, an important intracellular reactant against invading infectious
agents (5, 6); of IFN- (7), IL-12
(7, 8), IL-15 (9), MHC class I molecules,
ß2-microglobulin, TAP1, and LMP2 (10, 11), promoting macrophage activation, natural cytotoxicity, the
Th1 reaction, and CTL-mediated cytotoxicity (7, 8, 9, 10, 11, 12, 13, 14, 15). IRF-1
is induced by IFN-ß (16, 17), IFN-
(17), and IL-12 (18) in a positive feedback
loop that amplifies IFN effects. IRF-1 is also induced by other
cytokines, such as IL-6, leukemia inhibitory factor (19),
TNF, and IL-1 (20). It has also been reported that LPS
directly induces IRF-1 (21).
TNF and IFN- are proinflammatory cytokines critically involved in
LPS-induced mortality (22, 23). TNF is a proximal mediator
and is produced by macrophages as a result of direct LPS stimulation
(24). IFN- is a distal mediator and is produced by NK
cells stimulated by TNF (25, 26). In addition to TNF,
IL-10 and IL-12, also early products of LPS-stimulated macrophages
(27, 28), regulate the production of IFN- in response
to LPS with opposite effects, with IL-10 inhibiting and IL-12 promoting
IFN- production (27, 28, 29).
Given the role of IRF-1 in the expression of IFN- (7)
and the roles of LPS, TNF, and IFN- in the induction of IRF-1
(17, 20, 21), the possibility exists that IRF-1 occupies a
crucial position in the regulatory pathway that leads to LPS-induced
cytokine production and mortality. The aim of this study was to explore
the importance of IRF-1 in the pathogenesis of LPS-induced mortality
and other disease models mediated by TNF and IFN-. In this regard,
IRF-1 knockout (KO) mice were studied after the injection of LPS and in
a model of cerebral malaria, as models dependent on both TNF and
IFN- (22, 23, 30, 31), after the coinjection of LPS and
galactosamine (GalN), as a model dependent on TNF (32),
and after the injection of Con A, as a model dependent on IFN-
(33).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male and female C57BL/6 strain mice between 9 and 14 wk of age, homozygous for the deletion of the IRF-1 gene as previously described (3), were used throughout the study along with intact controls of matched sex, age, and strain. At the age of 6–8 wk, mice were transferred from the breeding facility (Taconic, Germantown, NY) to our facility where they were kept for 2–6 wk before use. Splenectomized and sham-splenectomized 8-wk-old female C57BL/6 mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and used at the age of 10 wk. Mice were housed in rooms maintained at constant temperature and humidity and subjected to a 12-h light/dark cycle. Mice received normal rodent chow (Purina, St. Louis, MO) and water ad libitum.
Induction of mortality and cytokine production with LPS, TNF, and
IFN-
Mortality and cytokine production were induced by the i.p.
injection of 10 mg/kg LPS (Escherichia coli 0111:B4; List
Biological Laboratories, Campbell, CA) or by the i.v. injection of 1.5
mg/kg murine TNF (Amgen, Thousand Oaks, CA) or by the i.v. coinjection
of 150 µg/kg murine IFN- (Amgen) and 50 µg/kg TNF. LPS, TNF, and
IFN- were dissolved in 200 µl saline. The doses of LPS and TNF for
use alone were chosen because in preliminary experiments they were
found to be close to LD100. Since IFN- was not
found to induce any mortality at doses up to 10 mg/kg, and since IRF-1
KO mice appeared to be susceptible to TNF-induced mortality similarly
to control mice (see below), IFN- direct toxicity was estimated as
the ability to confer lethality onto a nonlethal dose of TNF.
Therefore, the maximal nonlethal dose of TNF was preliminarily
established along with the dose of IFN- that, added to TNF maximal
nonlethal dose, was the closest to LD100. After
the administration of LPS, TNF, or IFN- and TNF, mice were monitored
for survival every 6, 12, or 24 h or sacrificed for blood and
spleen collection.
In vitro induction of cytokine production by spleen cells with LPS
Mice were sacrificed, and the spleens were removed and disrupted to yield a cell suspension. Cells were washed in RPMI 1640 medium (Life Technologies, Gaithersburg, MD), and mononuclear cells were separated on Histopaque 1083 (Sigma), washed in RPMI 1640, adjusted to a final concentration of 106/ml in RPMI 1640 with 5% FCS, 20 mM HEPES, 2 mM glutamine, penicillin, and streptomycin (Life Technologies), and cultured in duplicate at 37°C in 5% CO2 in the absence or presence of a dose range of LPS for 4 h. Culture supernatants were then collected and tested for TNF, IL-10, and IL-12.
Induction of mortality with LPS and GalN, Con A, or plasmodial infection
Mortality was induced by the i.p. injection of 1 µg/kg of LPS along with 0.9 g/kg GalN (Sigma) or by the i.v. injection of 20 mg/kg Con A (Sigma) or by the i.p. injection of 106 RBC parasitized with Plasmodium berghei ANKA. LPS and GalN were dissolved in 200 µl saline and so was Con A. Also the parasitized RBC were resuspended in 200 µl saline before injection. These doses of LPS and GalN and Con A used were chosen because in preliminary experiments they were found to be close to LD100. Infection with P. berghei ANKA results in cerebral malaria in susceptible strains of mice like the C57BL/6 (34). After the administration of LPS and GalN and after the administration of Con A, mice were monitored for survival every 3 h for the first 12 h and then at the 24th and 48th hour. After infection with P. berghei ANKA, mice were monitored daily for the appearance of signs of cerebral malaria and for survival and bled on day 7 by tail nick to assess parasitemia.
Measurement of cytokines
TNF, IFN-, IL-10, and IL-12 were measured in duplicate by
ELISA using commercially available kits (Biosource International,
Camarillo, CA). TNF, IL-10, and IL-12 were measured in serum collected
1.5 h after the administration of LPS, whereas IFN- was
measured in serum collected 6 h after the administration of LPS.
These time points were chosen for being those at which cytokines peak
after the injection of LPS or TNF, as others have reported (29, 35, 36, 37) and we tested in preliminary experiments (data not
shown). TNF was also measured in the culture supernatant of spleen
mononuclear cells. OD were quantitated in a Thermomax ELISA reader
(Molecular Devices, Menlo Park, CA), and results were finally expressed
in pg/ml.
Measurement of cytokine mRNA
Cytokine mRNA were measured by RNase protection assay in spleens
and livers. TNF, IL-10, and IL-12 (p40 chain) mRNA were measured in
organs collected 1.5 h after the administration of LPS, whereas
IFN- mRNA was measured in spleens collected 6 h after the
administration of LPS. After storage at -80°C, organs were
homogenized, and total RNA was extracted using the RNA Stat-60 solution
(Tel-Test, Friendswood, TX) according to the manufacturer’s
instructions. Extracted RNA was quantitated by spectrophotometry. For
RNase protection assay, antisense riboprobes were prepared by in vitro
transcription of cloned DNA templates with either SP6 (for TNF,
IFN-, and IL-10 mRNA) or T7 (IL-12 (p40 chain) mRNA and 18S RNA) or
T3 (cyclophilin mRNA) RNA polymerases (Ambion, Austin, TX) labeled with
[-32P]UTP and purified by PAGE and elution
in ammonium acetate buffer containing EDTA and SDS. Five micrograms of
organ-extracted RNA were hybridized overnight at 55°C with
105 cpm of each labeled riboprobe.
Unhybridized RNA was digested with RNases A and T1 (Ambion) for
1.5 h at 37°C. Hybridized and RNase-protected RNA was
precipitated, washed, and electrophoresed on polyacrylamide gel.
Hybrids containing cytokine mRNA were electrophoresed with hybrids
containing house-keeping RNA (18S RNA for spleen TNF and IFN- mRNA
and cyclophilin mRNA for liver TNF and spleen and liver IL-10 and IL-12
(p40 chain) mRNA). The radioactivity of the riboprobes in the hybrids
was quantitated by a PhosphorImager (Molecular Dynamics, Sunnyvale,
CA), and cytokine to housekeeping riboprobe radioactivity ratios were
calculated.
Spleen, lymph node, and blood cell counts
Mice were sacrificed, and spleens, lymph nodes, and blood were collected. Spleens were weighed and disrupted to yield a cell suspension. Spleen cells were counted with a H1E cell counter (Technicon, Tarrytown, NY). Percentages of spleen macrophages and NK cells were derived by direct immunofluorescence staining and FACS analysis with a FACScan flow cytometer (Becton Dickinson, Lincoln, NY). Macrophages were identified using an anti-F4/80 (A3–1; Serotec, Oxford, U.K.) and an anti-CD11b mAb (M1/70; PharMingen, San Diego, CA) and NK cells using an anti-NK1.1 mAb (PK136; PharMingen). Lymph nodes (cervical, axillary, and inguinal from both sides of the body) were pooled and disrupted. Lymph node cells and white blood cells were then counted as above.
Statistical analysis
Times of survival were compared using the Gehan generalized
Wilcoxon rank sum test. Prevalences of mortality and cerebral malaria
were compared using the 
2 test with continuity
correction factor. Results were expressed as mean (SD), and in the
figures illustrating cytokine levels, bars and lines indicate the
means, whereas error bars indicate the SD. Differences between groups
were tested by the Student t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in IRF-1 KO mice
IRF-1 KO mice were fully protected against LPS-induced mortality.
All (17/17) IRF-1 KO mice survived a dose of LPS that was lethal in
95% (19/20) of control mice (Fig. 1
).
Serum levels of TNF and IFN- were 78 and 94% lower, respectively,
in the IRF-1 KO than those in control mice (Fig. 2). Levels of TNF mRNA were lower in the
liver of IRF-1 KO than those in control mice but did not significantly
differ in the spleen between the two groups (Table I). Splenic levels of IFN- mRNA were
much lower in the IRF-1 KO mice than those of controls (Table I). Serum
levels of IL-10 and IL-12 were lower (49 and 37%, respectively) in the
IRF-1 KO than those of control mice (Fig. 2). Levels of IL-10 and IL-12
(p40 chain) mRNA were lower in the liver of IRF-1 KO than those of
control mice, although in the spleen they were not significantly
different between the two groups (Table I). IRF-1 KO mice were
similarly susceptible to controls to the mortality induced by a lethal
dose of TNF (Table II). IRF-1 KO mice
were also similarly susceptible to controls to the mortality induced by
the combination of a nonlethal dose of TNF with one of IFN-
(Table III).
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The production of TNF by spleen mononuclear cells stimulated in
culture by different doses of LPS was not significantly different
between IRF-1 KO and control mice (Fig. 3). However, the production of IL-10 and
IL-12 was lower in the IRF-1 KO than control mice when stimulated by
doses of LPS higher than 0.1 µg/ml.
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IRF-1 KO mice showed smaller spleens than controls (mean (SD)
38 ± 11 vs 62 ± 15 mg, n = 5,
p < 0.02], which contained considerably fewer cells
(Table IV). The percentage of macrophages
was not significantly different between IRF-1 KO and control mice,
whereas the percentage of NK cells was lower in the IRF-1 KO than in
controls (Table IV). However, the absolute counts of both macrophages
and NK cells were lower in the IRF-1 KO compared with control mice
(Table IV). IRF-1 KO mice also had fewer lymph node cells than controls
but had white blood cell counts similar to those of controls
(Table IV).
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After LPS administration, serum levels of TNF, IL-10, and IL-12
were significantly lower in splenectomized mice than in
sham-splenectomized controls (Fig. 4).
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IRF-1 KO mice survived longer after the coinjection of LPS and
GalN than control mice, even if eventually mortality prevalence was not
significantly different between the two groups (Fig. 5). In contrast, IRF-1 KO mice were
entirely protected against Con A-induced mortality. All (15/15) IRF-1
KO mice survived a dose of Con A that was lethal in 100% (15/15) of
control mice (Fig. 6). IRF-1 KO mice were
also protected against cerebral malaria, although partially. The
prevalence of cerebral malaria was lower in IRF-1 KO mice (4/10) than
in controls (10/10) (p < 0.02), and also the
progress of cerebral malaria to mortality was slower in the IRF-1 KO
mice that developed this condition than in controls
(p < 0.01). Thus, IRF-1 KO mice survived
P. berghei ANKA infection longer than controls (Fig. 7). However, on the seventh day of
infection, IRF-1 KO mice had parasitemia counts higher than those of
controls (mean (SD) 17.9 ± 3.5 vs 9.7 ± 3.1,
n = 10, p < 0.001).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. In these mice,
the decrease in TNF and IFN- production appears due to a
down-regulation of gene expression as well as to a reduction in the
number of spleen cells.
Injection of LPS to mice results in mortality via the triggering of a
lethal cytokine cascade (38). TNF and IFN- are central
mediators of the lethal action of LPS, and neutralization of either
cytokine has protective effects (22, 23). LPS first
induces the production of TNF by cells of the monocyte/macrophage
lineage (24), and then TNF induces the production of
IFN- from NK cells (25, 26, 27).
IRF-1 KO mice are totally protected against a dose of LPS that is
lethal in 95% of control mice. This protection is accompanied by a
decrease in the circulating levels of TNF and IFN-. IRF-1 KO mice,
however, are not protected against a lethal dose of TNF or against a
dose of IFN- that confers lethality in combination with a nonlethal
dose of TNF. Thus, the lack of IRF-1 protects against LPS-induced
mortality by impairing the production of the proinflammatory cytokines
TNF and IFN- and not by directly protecting against TNF and
IFN-.
The reduction in serum TNF and IFN- is accompanied by a reduction in
mRNA in the spleen or the liver, indicating that down-regulation of
gene expression may account for the decrease of these cytokines in the
circulation. TNF mRNA is reduced in the liver but not in the spleen of
IRF-1 KO mice. Consistent with this finding of unchanged expression of
the TNF gene in the spleen in vivo is the one that
splenocytes from IRF-1 KO or control mice in culture produce similar
quantities of TNF upon stimulation with LPS. This indicates that the
lack of IRF-1 does not compromise LPS-induced TNF production in the
spleen, whereas it does in the liver, confirming the existence of
differences in LPS-induced TNF production among macrophage subsets in
the body (39). IRF-1 KO mice have a reduced number of
cells in the spleen as well as in the lymph nodes. Compared with
controls, the spleens from IRF-1 KO mice contain a similar percentage
but lower absolute number of macrophages and a lower percentage and
absolute number of NK cells. Thus, in addition to down-regulation of
gene expression, an absolute reduction in the number of spleen
macrophages may account in the IRF-1 KO mice for the decrease in the
production of TNF. This possibility is supported by the fact that
splenectomized mice develop lower serum TNF levels than controls in
response to LPS. Similarly, an absolute reduction in the number of NK
cells may also contribute to the decrease in the production of
IFN-.
IL-10 and IL-12 are, like TNF, early products of LPS-stimulated
macrophages (28, 29). IL-10 and IL-12 have been shown to
regulate LPS-induced IFN- production at the level of gene expression
with opposite effects (27, 28, 29). Thus, an increase in IL-10
or a decrease in IL-12 production would result in a decrease in IFN-
and IFN- mRNA. Serum levels of both IL-10 and IL-12 are reduced to
similar extent in IRF-1 KO mice after LPS administration, indicating
that the down-regulation of the expression of the IFN-
gene in the spleens of IRF-1 KO mice after LPS is not due to an altered
balance between these two cytokines. Therefore, IFN- gene
expression may be down-regulated in IRF-1 KO mice after LPS
administration because of the combination of reduction in TNF, which
stimulates IFN- gene transcription (25, 26, 27),
and the lack of IRF-1, which is instrumental for IFN-
gene transcription (7). The reduction in IL-10 and IL-12
serum levels is accompanied by a reduction in mRNA in the liver,
although not in the spleen. This indicates that, similar to TNF, the
reduction in circulating IL-10 and IL-12 is due to down-regulation of
gene expression, at least in the liver. However, at variance with TNF,
splenocytes from IRF-1 KO mice in culture produce less IL-10 and IL-12
than control splenocytes after stimulation with high doses of LPS.
Thus, the lack of IRF-1 seems to compromise IL-10 and IL-12 production
in the spleen as well as in the liver, even if this is not immediately
shown by the splenic levels of mRNA induced by LPS in vivo. Again, in
similarity to TNF, in addition to down-regulation of gene expression,
the absolute reduction in the number of spleen macrophages may account
for the decrease in the production of IL-10 and IL-12. The observations
of reduced serum IL-10 and IL-12 levels in splenectomized mice after
the administration of LPS validate this possibility.
Results consistent with those found studying LPS-induced mortality were
obtained studying additional models of experimental pathology mediated
by TNF and IFN-. The coinjection of LPS and GalN results in hepatic
failure in mice (40). In this model, which is
TNF-dependent and IFN--independent, LPS-induced TNF triggers
hepatocyte apoptosis, a phenomenon enhanced by GalN-arrested gene
transcription (32). Although only temporarily, IRF-1 KO
mice are protected against the mortality brought about by LPS and GalN.
It is possible that the reduced production of TNF induced in these mice
by LPS is sufficient to cause a slight prolongation in survival,
although a decrease in mortality is not observed. The injection of Con
A also results in hepatic failure in mice (41). In this
model, which is TNF independent and IFN- dependent, Con A-induced
IFN- triggers hepatocyte apoptosis with involvement of the Fas-Fas
ligand system (33). IRF-1 KO mice are completely protected
against the mortality brought about by Con A. Cerebral malaria develops
in C57BL/6 mice upon infection with P. berghei ANKA
(34). Similar to LPS-induced mortality, both TNF and
IFN- are central mediators of this model, and neutralization of
either cytokine has protective effects (30, 31). IRF-1 KO
mice are protected against the development of cerebral malaria. Thus,
cerebral malaria is another disease model whose incidence and severity
are reduced in IRF-1 KO mice (42). However, IRF-1 KO mice
develop higher parasitemia than intact mice. It seems, therefore, that,
although intact mice mount a strong immune response against the
plasmodial parasite, resulting in cerebral malaria but also in the
control of parasitemia, IRF-1 KO mice mount an impaired response with
less development of cerebral malaria but also with less control of
parasitemia. Thus, IRF-1 plays a role in the immune response against
P. berghei by balancing the beneficial clearance of
parasites and related detrimental pathology. These results confirm the
importance of IRF-1 in immunity against intracellular microorganisms
(5, 7).
In conclusion, the IRF-1 KO mice illustrate that IRF-1 plays a role in
the pathogenesis of disease models mediated by the proinflammatory
cytokines TNF- and IFN- and suggest that IRF-1 represents a
potential therapeutic anti-inflammatory target.
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Footnotes |
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2 Abbreviations used in this paper: IRF-1, IFN regulatory factor-1; GalN, galactosamine; KO, knockout.
Received for publication December 9, 1998. Accepted for publication September 30, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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interferon antibodies prevent experimental cerebral malaria and its TNF overproduction. Proc. Natl. Acad. Sci. USA 86:5572.-/- mice, but not in TNF- -/- mice. J. Immunol. 159:1418.[Abstract]
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O. Gorgette, A. Existe, M. I. Boubou, S. Bagot, J.-L. Guenet, D. Mazier, P.-A. Cazenave, and S. Pied Deletion of T Cells Bearing the V{beta}8.1 T-Cell Receptor following Mouse Mammary Tumor Virus 7 Integration Confers Resistance to Murine Cerebral Malaria Infect. Immun., July 1, 2002; 70(7): 3701 - 3706. [Abstract] [Full Text] [PDF]
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A. De Creus, K. Van Beneden, F. Stevenaert, V. Debacker, J. Plum, and G. Leclercq Developmental and Functional Defects of Thymic and Epidermal V{gamma}3 Cells in IL-15-Deficient and IFN Regulatory Factor-1-Deficient Mice J. Immunol., June 15, 2002; 168(12): 6486 - 6493. [Abstract] [Full Text] [PDF]
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C. W. Wieland, B. Siegmund, G. Senaldi, M. L. Vasil, C. A. Dinarello, and G. Fantuzzi Pulmonary Inflammation Induced by Pseudomonas aeruginosa Lipopolysaccharide, Phospholipase C, and Exotoxin A: Role of Interferon Regulatory Factor 1 Infect. Immun., March 1, 2002; 70(3): 1352 - 1358. [Abstract] [Full Text] [PDF]
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J. Ko, A. Gendron-Fitzpatrick, and G. A. Splitter Susceptibility of IFN Regulatory Factor-1 and IFN Consensus Sequence Binding Protein-Deficient Mice to Brucellosis J. Immunol., March 1, 2002; 168(5): 2433 - 2440. [Abstract] [Full Text] [PDF]
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K. Streetz, B. Fregien, J. Plumpe, K. Korber, S. Kubicka, G. Sass, S. C. Bischoff, M. P. Manns, G. Tiegs, and C. Trautwein Dissection of the Intracellular Pathways in Hepatocytes Suggests a Role for Jun Kinase and IFN Regulatory Factor-1 in Con A-Induced Liver Failure J. Immunol., July 1, 2001; 167(1): 514 - 523. [Abstract] [Full Text] [PDF]
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 M. Goto, L. V. Deriy, Y. J. Chen, D. W. A. Beno, M. R. Uhing, V. A. Jiyamapa-Serna, and R. E. Kimura TNF-{alpha} increases sensitivity to LPS in chronically catheterized rats Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2857 - H2862. [Abstract] [Full Text] [PDF]
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C. A. Salkowski, K. E. Thomas, M. J. Cody, and S. N. Vogel Impaired IFN-{gamma} Production in IFN Regulatory Factor-1 Knockout Mice During Endotoxemia Is Secondary to a Loss of Both IL-12 and IL-12 Receptor Expression J. Immunol., October 1, 2000; 165(7): 3970 - 3977. [Abstract] [Full Text] [PDF]
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 J. C. G. Blanco, C. Contursi, C. A. Salkowski, D. L. DeWitt, K. Ozato, and S. N. Vogel Interferon Regulatory Factor (IRF)-1 and IRF-2 Regulate Interferon {gamma}-dependent Cyclooxygenase 2 Expression J. Exp. Med., June 19, 2000; 191(12): 2131 - 2144. [Abstract] [Full Text] [PDF]
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