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in Virus Infection-Induced Sensitization to Endotoxin1
Departments of
*
Pediatrics and
Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912; and
Division of Pediatric Pathology, Department of Pediatrics, College of Medicine and Public Health, Ohio State University, Columbus, OH 43210
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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2-fold for lethality and by 2- to 6-fold for serum TNF-
levels. Priming for LPS-induced TNF- was also seen with splenic and
peritoneal leukocytes isolated from infected mice and challenged with
LPS ex vivo. The effect on TNF- production was present in the
absence of IFN-
, its major producers NK and T cells, and the major
pathways for its induction through IL-12 and the signal transducer and
activator of transcription 4 (STAT4), and therefore was IFN-
independent. Early LCMV infection induces high concentrations of the
type 1 IFNs, IFN-
. Administration of recombinant IFN- alone
heightened the TNF- response to LPS. Innate IFN- and IFN-
responses to LCMV exist in a delicate balance. To reduce priming for
LPS-induced TNF- during LCMV, deficiencies in both the IFN-
and IFN- receptors or STAT1, a transcription factor downstream to
both IFNs, were required. These data demonstrate that early viral
infection can enhance sensitivity to bacterial products, and that this
sensitization can occur in part as a result of endogenously expressed
IFN-. This work also raises issues about potential complications
associated with IFN- therapies. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Key proinflammatory mediators required for a lethal response to
bacteria or endotoxin include TNF-, IFN-, and IL-12
(16, 17, 18, 19, 20). TNF- is a primary mediator of much of the
pathology leading to lethality from endotoxin (21, 22, 23, 24, 25, 26).
IFN- participates in this response by enhancing the sensitivity to
TNF- (27, 28, 29). IL-12 is important because it induces
IFN- (17, 18). Many reports have established that prior
exposure to IFN- can enhance the inflammatory and lethal effects of
endotoxin (19, 20, 30, 31). This has been demonstrated as
IFN--dependent priming to endotoxin in the Schwartzman reaction and
in dual challenge models using viral infection followed by superantigen
or endotoxin challenge (4, 11, 19). Viral infections are
potent stimuli for type 1 and/or type 2 IFNs (IFN- and/or
IFN-) (32, 33). Some viruses, such as LCMV, induce
primarily an early IFN- response, which can actively inhibit the
induction of IL-12 and, subsequently, IFN- (33, 34, 35).
Later during LCMV infection IFN- levels fall, and T cells become
prominent producers of IFN-. Exquisite sensitivity to a second
inflammatory challenge such as superantigen, IL-12, or endotoxin has
been demonstrated late during viral infections when T cells are
activated to become IFN--producing cells (3, 4, 11, 12). IFN- signaling results in the formation of activated
STAT1 homodimers, but IFN- signaling activates STAT1 and STAT2,
leading to the formation of STAT1 and STAT2 heterodimers and fewer
STAT1 homodimers. Thus, the IFNs can have some common functions
(32). The ability to potentiate the response to a second
inflammatory challenge may be such a function. However, little is known
about the impact of IFN- on LPS priming. IFN- are produced
early during many viral infections and are administered therapeutically
for chronic viral hepatitis (36). They are also being used
to augment the immune response in other infections and several
malignancies (37, 38, 39). Because of this, any similarity to
IFN- in terms of priming for second inflammatory challenges may be
important in complications during viral infections or IFN-
therapies.
LCMV infection provides a system in which the effects of IFN- or
IFN- on endotoxin sensitivity can be assessed because LCMV induces
an early IFN- response that actively inhibits IL-12 and IFN-.
Alternatively, in mice genetically deficient in IFN- signaling,
LCMV induces an early IFN- response (34, 35). In this
report we demonstrate that sensitization for endotoxin occurs early
during the innate response to LCMV. T, B, NK cells, IFN-, and IL-12
are not required. Early sensitization to endotoxin is mediated by
IFN-. Because IFN- can be induced in the absence of
LCMV-induced IFN-, both type 1 and 2 IFN functions must be
blocked to reduce this sensitization. This can be demonstrated in both
IFN- receptor-deficient or STAT1-deficient mice where
signaling for both type 1 and 2 IFNs is interrupted. These data
demonstrate for the first time that viral infection-induced IFN-
is capable of potentiating the response to endotoxin and, like IFN-,
may be a critical determinant of the outcome of septic shock. They also
suggest possible mechanisms for detrimental conditions resulting from
IFN- therapies.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All mice were housed in specific pathogen-free
conditions until initiation of experiments. The strains of mice used
included C57BL/6, 129 SvEv (Taconic Laboratory Animals and Services,
Germantown, NY). Mice genetically deficient in STAT1 on C57BL/6
background (STAT1-/-) and mice deficient in
IFN- and/or receptors (IFN-
R-/-, IFN- R-/-,
IFN- R-/-) on a 129SvEv background
were obtained from B & K Universal Limited (North Humberside, U.K.)
(IFN- R-/-) or from Dr. Joan Durbin at
Ohio State University (STAT1-/-, IFN-
R-/-, IFN-
R-/-) and bred here. E26 mice, deficient in NK
and T cells, were established with CBA x C57BL/6 backgrounds as
described (40). They were bred in strict isolation by
brother-to-sister mating in the animal care facility at Brown
University. T and B cell-deficient C57BL/6-recombination
activation gene 1 (RAG-1) mutants
(RAG-1-/-) mice were also bred at Brown
University (41). IFN--deficient and IL-12p40-deficient
mice on C57BL/6 background as well as their controls were obtained from
The Jackson Laboratory (Bar Harbor, ME). STAT4-deficient mice were
products of C57BL/6 and 129 breeding and were originally obtained from
Dr. J. Ihle, St. Jude’s Children’s Research Hospital (Memphis, TN)
and bred in our facility. Their C57BL/6 x 129
F2 controls were obtained from The Jackson
Laboratory.
Virus infection
Experiments were initiated on day 0 with mice either not infected or infected i.p. with 2 x 104 PFU of LCMV Armstrong strain clone E350 (34).
IFN- treatment
Animals were injected daily i.p. with 1 x
105 U of recombinant human IFN- A/D (IFN-),
active on all mouse cells, donated by Dr. Michael Brunda
(Hoffman-LaRoche, Nutley, NJ) or purchased from PBL Biomedical
Laboratories (New Brunswick, NJ), for 1 or 2 days before LPS challenge.
Vehicle treatment was 0.25 M ammonium acetate, 0.2 M NaCl at pH 2.5
diluted 1:140 in PBS (Brunda preparation) or PBS with 0.1% BSA (PBL
preparation).
NK cell depletion
NK depletion was achieved by pretreatment with anti-NK1.1 mAb (0.165 mg of PK136 mAb) on day -1 relative to LCMV infection. This protocol is >90% effective at removing NK cells from the spleen cell population (42, 43). Control animals were treated with similar preparations made with P3NS1 cells. Both reagents were purified in our laboratory from ascites fluid.
LPS treatments
Mice were injected i.p. with endotoxin (LPS) Escherichia
coli strain 0111:B4 (Difco, Detroit, MI) day 1 or 2 after virus or
IFN- treatments described above. The dose administered was
determined by the strain of mice used. C57BL/6 mice were much more
sensitive to LPS compared with 129 SvEv and mice >8 wk of age were
more sensitive compared with younger mice. For this reason, all
experiments were done using age-matched controls. A careful LPS dose
titration was performed to determine the optimal dose for age and
strain for experiments. For survival experiments using the C57BL/6
strain, all mice were 5–6 wk of age and received an LPS dose ranging
from 50, 75, and 100 µg. For serum TNF- experiments using C56BL/6
mice, 100 µg of LPS was injected; and for 129 SvEv mice, 200 µg of
LPS was injected.
Serum TNF-
Mice infected with virus or injected with IFN- on day 0 and
controls were injected with LPS i.p. on day 1 or 2. Blood was collected
1.5 and 6 h after LPS injection as well as from controls receiving
no LPS. Whole blood was centrifuged, and serum was decanted and stored
at -20°C.
Preparation of leukocytes for ex vivo LPS-induced TNF-
Mice infected with virus or injected with rIFN- on
day 0 and controls were sacrificed on day 1 or 2. Peritoneal leukocytes
were obtained by peritoneal lavage with 10 ml of cold sterile PBS.
Spleens were harvested and manually disrupted to obtain a single cell
suspension of splenic leukocytes. Peritoneal and splenic leukocytes
were briefly treated with NH4Cl to lyse
erythrocytes. Viability was confirmed by trypan blue exclusion. Splenic
and peritoneal leukocytes were cultured at 1 x
106 and 5 x 105
cells/well, respectively, in 96-well plates with a titration of LPS.
Ten-fold dilutions of LPS from 100 to 0.1 mg/ml were added to cells at
a 1:1 ratio. Therefore, the final concentrations of the culture
solution were half the concentration appearing on the figure legends.
Cells were cultured at 37°C for 24 h in RPMI 1640 plus 10% FBS;
supernatant was decanted and stored at -20°C. Due to low cell yields
per mouse, peritoneal cells were pooled from each group.
ELISA cytokine determination
TNF- and IFN- concentrations in serum and
leukocyte culture supernatant were determined by standard sandwich
ELISA. The capture Ab for TNF- was clone TN3-19.2 hamster
anti-mouse/rat TNF- (BD PharMingen, San Diego, CA). The
detection Ab was a polyclonal rabbit anti-mouse TNF- Ab
(Endogen, Woburn, MA). Limit of detection for diluted serum and culture
supernatant TNF- was 0.08 ng/ml. IFN- capture Ab was obtained
from ascites from clone XMG1.2. The detection Ab was rabbit polyclonal
anti-mouse IFN- supplied by Dr. Phillip Scott (University of
Pennsylvania, Philadelphia, PA). The limit of detection for diluted
samples was 0.08 ng/ml. Colorimetric changes of enzyme substrates were
detected at 405 nm wavelength using a Spectramax 250 reader (Molecular
Devices, Sunnyvale, CA).
Statistical analysis
Results are given as mean ± SEM. Two-tailed Student’s t tests were run on SigmaStat (SPSS, Chicago, IL). For survival studies, p values were obtained using the nonparametric Mantel-Cox test (Statview; Abacus Concepts, Berkeley, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To examine sensitivity to LPS during the innate response
to LCMV, LPS-induced lethality was assessed at day 2 of LCMV infection.
Day 2 was chosen because at that time point, LCMV induces high levels
of IFN- with low to undetectable levels of IFN- protein.
C57BL/6 mice were injected with 50, 75, or 100 µg of LPS i.p. and
observed for 14 days. Increased lethality was seen in LCMV-infected
mice compared with uninfected mice (Fig. 1
, A–D). Thus, underlying
early infection with LCMV resulted in increased sensitivity to
LPS.
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is induced by LPS and is required for LPS-induced
lethality. For this reason, it is presented here as an end-point to
represent the magnitude of the inflammatory response. LCMV-infected
mice were challenged at day 2 with i.p. LPS to examine inflammatory
cytokine production during this dual challenge. Increased LPS-induced
TNF- was observed in the serum of LCMV-infected compared with
uninfected mice (Fig. 2A).
Splenic and pooled peritoneal leukocytes from day 2 LCMV-infected mice
also produced more TNF- in response to ex vivo LPS stimulation
compared with those from uninfected mice (Fig. 2, B and
C). Therefore, LCMV sensitizes for both LPS-induced
lethality and TNF- production.
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independent
Because IFN- is known to contribute to lethality from
LPS, we used mice deficient in NK, T, and/or B cells to demonstrate
that early LCMV-induced sensitization for LPS can occur in the
absence of IFN--producing cells. Increased TNF- induction was
seen in LCMV-infected immunocompetent, E26 mice deficient in NK and T
cells, and RAG-1-/- mice deficient in T and B
cells (Table I). Ab-mediated NK depletion
also did not abolish virus-induced sensitization for LPS (Table I). In
addition, under conditions where all uninfected mice survived,
LCMV-infected E26 mice displayed similar LPS-induced lethality compared
with C57BL/6 controls (83 vs 100%). Thus, LCMV-induced sensitization
for LPS does not require the presence of T or NK cells, which are known
to be producers of IFN-.
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is generally IL-12 dependent via
signaling through STAT4 (44). By using mice genetically
deficient in either IL-12p40 or STAT4, unable to produce innate IFN-
in response to certain viral or LPS challenges, and by using
IFN--deficient mice, it was evident that virus-induced sensitization
for LPS can occur in the absence of IFN- (Table II). Taken together, these data indicate
that virus-induced sensitization for LPS does not require cells known
to produce IFN- or IFN- itself.
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induces increased sensitivity to LPS
Because IFN- is detectable at high levels in early LCMV
infection, we hypothesized that type 1 IFNs were responsible for
LCMV-induced priming for LPS response. To assess this, we injected
C57BL/6 mice with IFN- followed by LPS at day 2. LPS-induced
lethality was modestly higher in IFN--pretreated mice compared with
vehicle-treated mice (100 vs 70%). Serum TNF- levels
were higher in IFN--treated mice compared with those treated with
controls (Fig. 3A). Splenic
leukocytes and pooled peritoneal leukocytes obtained from mice 24
h after IFN- treatment were similarly sensitized to LPS (Fig. 3, B and C). These data indicate that IFN- can
sensitize for LPS.
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To determine whether IFN- induced early during LCMV
infection was responsible for sensitization for LPS, IFN-
R+/+ and IFN- R-/-
mice were injected with LPS at day 2 of LCMV infection. LPS priming for
TNF- was intact in LCMV-infected IFN-
R-/- mice (Fig. 4A).
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response in the absence of IFN- signaling
(35). This is evident here in LCMV-infected IFN-
R-/- mice who had higher serum IFN- compared
with IFN- R+/+ controls (510 ± 102 vs
84 ± 15 pg/ml) and IL-12p40 (2033 ± 178 vs 338 ± 47
pg/ml) (p < 0.05). To prove that virus-induced
IFN- revealed in this setting contributes to the sensitization for
LPS seen in the absence of IFN- signaling, the same experiment
was performed examining IFN- R+/+ (wild
type), IFN- R-/-, IFN-
R-/-, and IFN-
R-/- mice. Only when both IFN- and
IFN- signaling at the receptor level is interrupted is LPS induction
of TNF- reduced (Fig. 4
A). Importantly, priming in the
IFN- R-/- mice is intact, demonstrating
again that IFN- is not necessary for sensitization early in LCMV. A
similar pattern of priming was seen in splenic and pooled peritoneal
leukocytes isolated from LCMV-infected mice (Fig. 4, B and
C). These data demonstrate that either LCMV-induced
IFN- or IFN- revealed in the absence of IFN- signaling
can mediate sensitization for LPS. Only by blocking both IFNs can this
sensitization, as indicated by TNF- production, be reduced. A role for STAT1 in viral infection-induced sensitization for LPS
STAT1 is a transcription factor important to signaling
for both IFN- and IFN-. Because the above experiments indicate
that both IFN- and IFN- can contribute to virus-induced
sensitization for LPS, the role of signaling through their common
transcription factor, STAT1, was examined. Mice genetically deficient
in STAT1 provide a tool for assessing the importance of a pathway
common to both IFNs. Reduced sensitization for LPS in vivo and ex vivo
was observed during LCMV infection in STAT1-/-
compared with STAT1+/+ mice (Fig. 5, A–C). These data, like
that presented in IFN- R-/- mice, also
demonstrate that by disrupting IFN- and IFN- signaling,
LCMV-induced priming for LPS is significantly reduced.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2-fold increase in LPS-induced lethality
and a 2- to 6-fold increase in TNF- production were seen in
LCMV-infected compared with uninfected mice. Sensitization to LPS at
day 2 of LCMV, when high systemic levels of IFN- are present, did
not require the presence of T, B, NK cells or IFN-. IFN-
R-/- mice showed more sensitivity to LPS during
LCMV infection; however, in the absence of IFN- signaling, LCMV
induces IL-12 and IFN-, which are known to enhance the sensitivity
to LPS. For this reason, it was necessary to compare sensitization in
IFN- R+/+, IFN-
R-/-, and IFN-
R-/- mice to assess the role of IFN-. In
both the IFN- R+/+ and IFN-
R-/- mice sensitization was intact. Only in the
IFN- R-/- mice was priming reduced.
Mice deficient in STAT1, a transcription factor important in both
IFN- and IFN- signaling, also showed reduced priming for LPS
during LCMV infection compared with STAT1+/+
controls. Pretreatment of mice with IFN- sensitized to the effects
of LPS. These data demonstrate for the first time that IFN- can
play an underappreciated role in sensitization for LPS. These data demonstrate several important points concerning the immune cross talk between viral infection and bacterial challenge. There are many examples clinically of coupling of viral infection with serious bacterial infection such as influenza with severe bacterial pneumonia and varicella with severe secondary skin infections. The link between bacterial and viral infection traditionally has been explained as opportunistic. Host defenses are compromised by injury to skin and epithelial barriers during viral infection providing a portal of entry for secondary bacterial pathogens. Our data extend the understanding of the impact of immune activation by virus on the magnitude of the inflammatory response and ultimate outcome to bacterial challenge. It is possible that immune activation from common viral infections routinely shapes the magnitude of the immune response to more dangerous bacterial challenges. Because the magnitude of the inflammatory response early in septic shock has correlated well in humans to outcome, it is plausible that the host IFN response to underlying viral infection may be a critical determinant of outcome in septic shock as well as other severe inflammatory states.
Many studies have shown that IFN- can augment LPS-induced TNF-
production and lethality (19, 29, 30, 31). In fact, previous
work from this group demonstrated a 5- to 10-fold increase in TNF-
production and lethality from LPS when administered during the adaptive
immune response to LCMV (4). At this time, the immune
response to LCMV is characterized by the activation and expansion of
CD8 T cells, which are potent IFN- producers. LPS-induced lethality
during the adaptive response to LCMV infection required IFN-, NK,
and T cells (4). In this report we demonstrate that
IFN- induced early during the innate response to LCMV can also
augment LPS-induced lethality and TNF- production by 4- to 5-fold.
This pathway for sensitization to LPS is clearly different in that it
does not require IFN-, NK, or T cells. Although virus-induced
IFN- is less effective than IFN- at sensitization for LPS,
this work shows that viral infections can modulate the response to
secondary inflammatory challenges at times when either IFN is present.
The results raise important questions concerning potential detrimental
conditions resulting from high dose IFN- and IFN- therapy.
Importantly, in this in vivo model of virus-induced IFN-,
our group previously reported that blocking of IFN- signaling
revealed the production of an earlier alternative pathway for
virus-induced IL-12 and IFN- (34). Using this system,
these observations have been extended to the sensitization for LPS at
day 2 through either virus-induced IFN- or through virus-induced
IFN- revealed in the absence of IFN- signaling. This
observation is important for two reasons. First, it indicates
redundancy in the IFN response to LCMV revealing two different pathways
for enhancing sensitivity to endotoxin, which can only be examined by
in vivo analysis. Second, it provides important insight into the
mechanism of virus-induced sensitization for the response to LPS.
Because IFN- and IFN- can lead to priming, the pathways
involved must be common to both. Signaling through STAT1, used by both
IFN- and IFN-, must occur to maximize LCMV-induced priming.
These data point to molecular cross talk between IFN signaling and LPS
signaling in an in vivo system. Although the signaling pathways for
IFN-, IFN-, and LPS are well described, overlap between these
pathways has not been well defined (32). At what level
this overlap occurs is unclear; however, IFN signaling to the point of
activation of STAT1 is necessary for LPS priming. More importantly,
these data implicate IFN-activated STAT1 as a key regulator of the
magnitude of the response to LPS. This sequence of events may be
critical in determining the magnitude of the response to second
inflammatory challenges in viral infections as well as following the
therapeutic use of IFN-.
Although potentiation of the LPS response by IFN- has been
extensively documented, the mechanism for this is poorly understood
(19, 29, 30, 31, 45). Recently, Held et al. showed this and
observed that pretreatment of a macrophage cell line with IFN-
augmented LPS-induced DNA binding of NF-
B resulting in increased
expression of inducible NO synthase mRNA and nitrite production
(46). They did not determine a role for STAT1 in this
priming but their work does begin to elucidate a molecular pathway for
IFN- modulation of LPS signaling. Our work is the first to
demonstrate sensitization for LPS through virus-induced IFN- or
IFN- and that this sensitization requires STAT1.
Our results can be contrasted to those of Tzung et al., who
reported that IFN- protected from endotoxin-induced mouse mortality
(47). Those investigators chose different doses and types
of LPS. Moreover, they used either 1 h pretreatment, simultaneous,
or post-LPS treatment with recombinant IFN- to diminish mortality as
well as TNF- production by Kupffer cells. Their results may be
related to the studies from our group demonstrating that IFN- can
act to inhibit IL-12 induction (34) as well as
responsiveness to IL-12 for IFN- induction (35).
However, here we demonstrate that LCMV-induced IFN- signaling
through STAT1 enhances rather than inhibits the response to LPS. The
differences between the reported IFN- effects may be related to
dose, type, or timing of LPS. Although phosphorylation of STAT1 and its
binding to DNA occur quickly, the necessary events for endotoxin
sensitization may require more time than examined by Tzung et al.
Teleologically, the IFN--enhancing rather than -inhibitory
effects seen in LPS sensitization may exist to allow the host to
respond to overwhelming bacterial infections during virus-immune
activation.
We attempted to demonstrate decreased LPS-induced lethality
during LCMV infection in the absence of IFN signaling. The results of
these experiments were somewhat puzzling. LCMV infection alone was
nonlethal for IFN- R+/+, IFN-
R-/-, IFN- R-/-, and
IFN- R-/- mice. Although
LCMV-infected, LPS-treated IFN- R-/-
mice showed increased average survival times compared with
IFN- R+/+, IFN-
R-/-, and IFN- R-/-
mice, 100% lethality was eventually seen in all groups. Conversely,
pretreating with IFN- to increase LPS-induced lethality was at best
marginally successful (see Results). Thus, although IFNs
play an important role, these data indicate that other factors are also
promoting sensitization to LPS during viral infection.
In summary, these studies extend previous work from this group
describing immune modulation by underlying viral infection leading to
sensitization to a subsequent bacterial product challenge. Here, we
show that virus-induced sensitization to endotoxin can occur through
either IFN- or IFN- due to overlapping signaling through
STAT1. Thus, pathways for critical immune cross talk capable of
determining the magnitude and outcome of the response to sequential
inflammatory challenges are defined. In humans, the outcome of
bacterial septic shock correlates to the magnitude of the inflammatory
response. Thus, these studies suggest that underlying viral infection
leading to the induction of IFN- or IFN- or their therapeutic
administration resulting in STAT1 activation may be critical to outcome
by modulating the sensitivity to subsequent inflammatory stimuli.
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Acknowledgments |
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sera. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Christine A. Biron, Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University Box G-B629, Providence, RI 02912.
3 Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; RAG-1, recombination activation gene 1.
Received for publication September 21, 2000. Accepted for publication November 29, 2000.
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T. O. Yarovinsky, L. S. Powers, N. S. Butler, M. A. Bradford, M. M. Monick, and G. W. Hunninghake Adenoviral Infection Decreases Mortality from Lipopolysaccharide-Induced Liver Failure Via Induction of TNF-{alpha} Tolerance J. Immunol., September 1, 2003; 171(5): 2453 - 2460. [Abstract] [Full Text] [PDF]
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K. B. Nguyen, T. P. Salazar-Mather, M. Y. Dalod, J. B. Van Deusen, X.-q. Wei, F. Y. Liew, M. A. Caligiuri, J. E. Durbin, and C. A. Biron Coordinated and Distinct Roles for IFN-{alpha}{beta}, IL-12, and IL-15 Regulation of NK Cell Responses to Viral Infection J. Immunol., October 15, 2002; 169(8): 4279 - 4287. [Abstract] [Full Text] [PDF]
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Y.-C. Chen and S.-Y. Wang Activation of Terminally Differentiated Human Monocytes/Macrophages by Dengue Virus: Productive Infection, Hierarchical Production of Innate Cytokines and Chemokines, and the Synergistic Effect of Lipopolysaccharide J. Virol., August 28, 2002; 76(19): 9877 - 9887. [Abstract] [Full Text] [PDF]
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Z. Trobonjaca, A. Kroger, D. Stober, F. Leithauser, P. Moller, H. Hauser, R. Schirmbeck, and J. Reimann Activating Immunity in the Liver. II. IFN-{beta} Attenuates NK Cell-Dependent Liver Injury Triggered by Liver NKT Cell Activation J. Immunol., April 15, 2002; 168(8): 3763 - 3770. [Abstract] [Full Text] [PDF]
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T. R. Johnson, S. Hong, L. Van Kaer, Y. Koezuka, and B. S. Graham NK T Cells Contribute to Expansion of CD8+ T Cells and Amplification of Antiviral Immune Responses to Respiratory Syncytial Virus J. Virol., March 27, 2002; 76(9): 4294 - 4303. [Abstract] [Full Text] [PDF]
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L. Malmgaard, T. P. Salazar-Mather, C. A. Lewis, and C. A. Biron Promotion of Alpha/Beta Interferon Induction during In Vivo Viral Infection through Alpha/Beta Interferon Receptor/STAT1 System-Dependent and -Independent Pathways J. Virol., March 27, 2002; 76(9): 4520 - 4525. [Abstract] [Full Text] [PDF]
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V. M. Jovasevic and M. B. Mokyr Melphalan-Induced Expression of IFN-{beta} in MOPC-315 Tumor-Bearing Mice and Its Importance for the Up-Regulation of TNF-{alpha} Expression J. Immunol., November 1, 2001; 167(9): 4895 - 4901. [Abstract] [Full Text] [PDF]
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, Below level of
detection, which was 80 pg/ml.
