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14+NKT Cells in Lipopolysaccharide-Induced Lethal Shock in Mice1
* Department of Immunology, Max-Planck-Institute for Infection Biology, Berlin, Germany; and
Department of Bacteriology, Nara Medical University, Nara, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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14+NKT cells. To assess the relative contributions
of these NK1+ cells to LPS-induced shock, we compared the
susceptibility to LPS-induced shock of 
2-microglobulin
(2m)-/- mice that are devoid of
V14+NKT cells, but not NK cells, with that of wild-type
(WT) mice. The results show that 2m-/-
mice were more susceptible to LPS-induced shock than WT mice. Serum
levels of IFN-
following LPS challenge were significantly higher in
2m-/- mice, and endogenous IFN-
neutralization or in vivo depletion of NK1+ cells rescued
2m-/- mice from lethal effects of LPS.
Intracellular cytokine staining revealed that NK cells were major
IFN- producers. The J281-/- mice that are
exclusively devoid of V14+NKT cells were slightly more
susceptible to LPS-induced shock than heterozygous littermates. Hence,
LPS-induced shock can be induced in the absence of
V14+NKT cells and IFN- from NK cells is involved in
this mechanism. In WT mice, hierarchic contribution of different cell
populations appears likely. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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from macrophages and IFN- from
NK1+ cells, play a key role in the disease
process (3). The uncontrolled production of
proinflammatory cytokines causes several pathophysiological reactions,
which ultimately form the septic shock syndrome, often with fatal
outcome (4). Because TNF- and IFN- are central to
lethality in experimental endotoxic shock, neutralization of these
cytokines decreases mortality (3, 4, 5, 6, 7, 8). The critical role of
these cytokines in the pathogenesis of LPS-induced shock was confirmed
using mice deficient for either of these cytokine receptors
(9, 10, 11).
NK1+ cells segregate into two major populations,
namely NKT cells and NK cells. NKT cells represent a unique T cell
subset which expresses NK cell markers such as NKR-P1 (NK1.1)
(12). The development of a majority of NKT cells depends
on 2-microglobulin
(2m)3-associated CD1d
and hence, 2m-/- and
CD1d-/- mice are devoid of this cell population
(12, 13, 14, 15, 16, 17). These NKT cells express V14/J281 gene
segments (12), and they are abundant in the liver
(13, 14, 18). Upon stimulation, these
V14+NKT cells promptly secrete large amounts
of type 1 and 2 cytokines, IFN- and IL-4, respectively (14, 19, 20, 21, 22, 23, 24). In contrast, NK cells develop independently of
2m and produce IFN-, but not IL-4
(25), although these cells are also abundant in the liver
(26). Accumulating evidence suggests that
NK1+ cells participate in the pathogenesis of
LPS-induced lethal shock (27, 28). However, it remains
elusive whether either NK cells, NKT cells, or both are involved in the
disease process, although a major contribution of
V14+NKT cells has recently been concluded from
different experimental mouse models (29, 30, 31).
In the present study, we assessed the relative contributions of NK
cells and NKT cells in the pathogenesis of LPS-induced lethal shock
using V14+NKT cell-deficient mice. Our
findings point to NK rather than V14+NKT cells
as major players in LPS-induced shock. We assume that different cell
populations contribute to septic shock in a hierarchic fashion.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2m-/- mice were
purchased from The Jackson Laboratory (Bar Harbor, ME).
J281-/- mice were kindly provided by Dr. M.
Taniguchi (Chiba University, Chiba, Japan) (32). These
mutants backcrossed onto C57BL/6
(2m-/-, >15th
generation; J281-/- and
J281+/-, >6th generation) and C57BL/6 mice
were maintained under specific pathogen-free conditions at our animal
facilities (Max-Planck-Institute, Berlin, Germany). Carefully
weight- and generation-matched female mice were used at 8–10 wk
of age.
Antibodies
mAbs against CD3
(145-2C11), FcR (2.4G2), IFN- (R4-6A2
and XMG1.2), IL-4 (11B11), and IL-12 (p40) (C17.8 and C15.6.7) were
purified from hybridoma culture supernatants. Anti-IFN- mAb (XMG1.2)
and anti-IL-12 (p40) mAb (C15.6.7) were biotinylated, and
anti-CD3 mAb was conjugated with FITC by standard methods.
Biotinylated anti-NK1.1 mAb, PE-conjugated rat IgG1 mAb (R3-34),
mouse IgG2a mAb (G155-178), rat IgG1 (R3-34), and PE-conjugated
anti-IFN- mAb (XMG1.2) were purchased from BD PharMingen
(Hamburg, Germany). Hamster IgG was obtained from Dianova (Hamburg,
Germany).
LPS and septic shock
Salmonella typhimurium-derived LPS was purchased from
Sigma-Aldrich (Deisenhofen, Germany). Highly purified Salmonella
abortus equi-derived LPS was kindly provided by Dr. M. A.
Freudenberg (Max-Planck-Institute for Immunobiology, Freiburg,
Germany). Endotoxic shock and the generalized Shwartzman reaction were
induced in mice as indicated in the table or figure legends. For
neutralization of endogenous IFN- or IL-4, mice received i.p. 500
µg anti-IFN- mAb (XMG1.2) or 1 mg anti-IL-4 mAb,
respectively, 2 h before LPS challenge. For in vivo depletion of
NK1+ cells, mice were treated i.p. with 500 µg
anti-NK1.1 mAb 3 or 4 days before LPS challenge.
ELISA
For detection of IFN- and IL-12, serum samples were incubated
in immunoassay plates (Nunc, Copenhagen, Denmark) precoated with 5
µg/ml anti-IFN- mAb (R4–6A2) or 10 µg/ml anti-IL-12
(p40) mAb (C17.8), respectively. After washing, plates were incubated
with 2 µg/ml biotinylated anti-IFN- mAb (XMG1.2) or 5 µg/ml
biotinylated anti-IL-12 (p40) mAb (C15.6.7), respectively, followed
by streptavidin (SA)-conjugated alkaline phosphatase (Dianova) and the
chromogen p-nitrophenyl phosphate (Sigma-Aldrich). The
cytokine concentration in each sample was determined using serially
diluted mouse rIFN- (R&D Systems, Wiesbaden, Germany) or mouse
rIL-12 (Genzyme, Alzenau, Germany). The detection limits were 1.56 U/ml
and 0.625 ng/ml, respectively. Serum levels of TNF-, IL-6, IL-10,
and IL-18 were assayed using the Quantikine M kit (R&D Systems) and the
detection limits were 5.1, 3.1, 4.0, and 8.0 pg/ml, respectively.
Cell preparation and cell surface phenotype analysis
Liver mononuclear cells (LMNC) and splenocytes were prepared as described previously (14). After blocking, cells were stained with conjugated mAbs. Biotinylated mAb was visualized with SA-conjugated Red 670 (Life Technologies, Gaithersburg, MD). After washing, cells were fixed with 1% paraformaldehyde. Stained cells were acquired by FACScan (BD Biosciences, Mountain View, CA) and analyzed with CellQuest software (BD Biosciences).
Intracellular cytokine staining
LMNC were incubated in the presence of brefeldin A (5 µg/ml;
BD PharMingen) for 3 h, and then stained with FITC-conjugated
anti-CD3 mAb and biotinylated anti-NK1.1 mAb followed by
SA-conjugated Red 670. After fixation with 2% paraformaldehyde and
permeabilization with 0.5% saponin (Sigma-Aldrich), intracellular
cytokine staining was performed using PE-conjugated anti-IFN-
mAb. PE-conjugated rat IgG1 mAb was used as a control. Stained cells
were acquired by FACScan and analyzed with CellQuest software.
Statistical analysis
The statistical significance was determined by either log-rank test (survival time) or Student’s t test (serum cytokine levels). A p value <0.05 was regarded as significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2m-/- mice are more susceptible to
LPS-induced lethal shock than WT mice
We compared 2m-/-
and C57BL/6 mice for susceptibility to LPS-induced lethal shock. Mice
were challenged with various doses of LPS and survival times were
monitored thereafter. All C57BL/6 mice examined survived when
challenged with 150 µg LPS (Table I
),
although they displayed signs of severe endotoxemia. In contrast, all
2m-/- mice succumbed
to the shock within 100 h; this was also true even after challenge
with 100 µg LPS (Table I). Similar results were obtained with highly
purified S. abortus equi-derived LPS (data not shown),
verifying that the reaction was induced by LPS but not other
contaminating components, such as lipoprotein, present in commercially
obtained LPS (33). Thus,
2m-/- mice were more
susceptible to LPS-induced lethal shock than WT mice.
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following LPS challenge are higher in
2m-/- mice than in WT mice
Serum levels of TNF- and IFN- in
2m-/- and C57BL/6 mice
following LPS challenge (150 µg) were compared. Because contribution
of IL-12, IL-6, IL-10, and IL-18 to LPS-induced shock has been
suggested (3, 34, 35), serum levels of these cytokines
were also analyzed. Serum levels of TNF-, IL-12 (p40), IFN-,
IL-6, IL-10, or IL-18 in C57BL/6 mice peaked at 1, 4, 6, 3, 2, or
1 h, respectively, after LPS challenge (data not shown).
Therefore, we compared cytokine levels in the sera of
2m-/- and C57BL/6 mice
at these time points. Serum levels of TNF-, IL-12 (p40), IL-6,
IL-10, and IL-18 following LPS challenge were comparable between
2m-/- and C57BL/6 mice
(Fig. 1, A, B, and
D–F). In contrast, serum levels of IFN- at 6 h
following LPS challenge were significantly higher in
2m-/- mice than in
C57BL/6 mice (Fig. 1C); this was also true at different time
points following LPS challenge (data not shown). These results suggest
that 2m influences IFN- production
following LPS challenge.
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neutralization prevents LPS-induced lethal shock
in both 2m-/- and C57BL/6 mice
We examined whether IFN- or IL-4 participates in induction or
inhibition, respectively, in LPS-induced lethal shock. Mice were
treated with anti-IFN- mAb or anti-IL-4 mAb 2 h before
LPS challenge and survival times were monitored thereafter. All
2m-/- mice examined
were protected against LPS-induced lethal shock by endogenous IFN-
neutralization when challenged with 200 µg LPS (Table I
). Similar
results were obtained in C57BL/6 mice when challenged with 250 µg LPS
(Table I). In contrast, the susceptibility of C57BL/6 mice to
LPS-induced lethal shock was virtually unaffected by endogenous IL-4
neutralization (Table I). IL-4 does not seem to inhibit LPS-induced
shock. In contrast, IFN- participates in LPS-induced lethal shock
independent from the presence or absence of
2m-dependent immune mechanisms.
In vivo depletion of NK1+ cells prolongs survival time
and reduces serum levels of IFN- in mice following LPS challenge
Mice were treated with anti-NK1.1 mAb 3 days before LPS
challenge and survival times were monitored thereafter. Depletion of
NK1+ cells by anti-NK1.1 mAb treatment was
verified by flow cytometry (data not shown). The
2m-/- mice were
rescued from lethal shock by NK1+ cell depletion
when challenged with 100 µg LPS (Table I). In vivo depletion of
NK1+ cells prolonged the survival times of
2m-/- mice following
150 µg LPS challenge (Table I). Similar results were obtained in
C57BL/6 mice challenged with 200 or 250 µg LPS, respectively (Table I). Consistent with the prolonged survival time, in both mouse strains
serum levels of IFN- following LPS challenge were significantly
(p < 0.02), though not completely, reduced by
NK1+ cell depletion (data not shown). These
results suggest that NK1+ cells other than
V14+NKT cells participate in the pathogenesis
of LPS-induced lethal shock and that IFN- is produced by
2m-independent NK1+
cells following LPS challenge.
NK cells are major IFN- producers in
2m-/- mice as well as in C57BL/6 mice
following LPS challenge
We attempted to identify the source of IFN- in
2m-/- and C57BL/6 mice
following LPS challenge. Because the liver is one of the target organs
of LPS, the frequencies of IFN--producing cells among LMNC were
determined by intracellular cytokine staining. High frequencies of
IFN--producing cells were detected among
CD3-NK1+ cells in
2m-/- mice, which were
higher than those in C57BL/6 mice (Fig. 2). Considerable numbers of IFN-
producers were also detected among
CD3+NK1+ cells in both
2m-/- and C57BL/6
mice. In contrast, frequencies of IFN- producers among
CD3-NK1- cells in both
mouse strains were low. A distinct population of IFN- producers was
identified among CD3+NK1-
cells in 2m-/-, but
not C57BL/6, mice (Fig. 2). Note that the intensity of IFN- staining
among CD3-NK1+ cells was
markedly higher than that among other cell populations. Consistent with
previous findings (13, 14), high frequencies of
CD3+NK1+ cells were
detected in the liver of C57BL/6 mice, but frequencies were markedly
reduced in 2m-/- mice
(Fig. 2; Table II). In contrast, the
proportion of CD3-NK1+
cells was 
2-fold higher in the liver of
2m-/- mice compared
with C57BL/6 mice (Fig. 2; Table II). Because absolute numbers of
CD3-NK1+ cells
significantly exceeded those of
CD3+NK1+ cells remaining in
2m-/- mice (see Table II), our results suggest that NK cells, rather than NKT cells, are
major IFN- producers in
2m-/- mice following
LPS challenge.
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281-/- mice are more susceptible to LPS-induced
shock than J281+/- mice and in vivo depletion of
NK1+ cells prevents J281-/- mice from
LPS-induced lethal shock
To directly determine whether V14+NKT
cells participate in LPS-induced lethal shock, we compared the
susceptibility of J281-/- and
J281+/- mice to LPS-induced shock. Both
J281-/- and
J281+/- mice succumbed to the shock when
challenged with 300 µg LPS within 30 and 40 h, respectively,
whereas both groups of mice survived the shock induced by challenge
with 200 µg LPS (Table III). All
J281-/- mice succumbed to the shock within
40 h when challenged with 250 µg LPS, whereas all
J281+/- mice survived the challenge (>1 wk),
although they showed profound signs of endotoxemia (Table III). Thus,
J281-/- mice were slightly more susceptible
to LPS-induced shock than J281+/- mice. In
vivo depletion of NK1+ cells rescued
J281-/- mice from LPS-induced lethal shock
(Table III). These results not only argue against a major contribution
of V14+NKT cells in LPS-induced shock, but
also suggest that NK1+ cells other than
V14+NKT cells play a critical role in lethal
consequences of LPS.
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producers in
J281-/- mice following LPS challenge
We attempted to identify the cellular source of IFN- in
J281-/- mice following LPS challenge. High
frequencies of IFN- producers were detected among
CD3-NK1+ cells in the
liver of J281-/- mice (Fig. 2). Note that
the frequencies of IFN- producers among
CD3-NK1+ cells were lower
in J281-/- mice than in C57BL/6 and
2m-/- mice.
Considerable numbers of IFN- producers were also detected among
CD3+NK1+ cells remaining in
J281-/- mice (Fig. 2), indicating that
unconventional NKT cells lacking V14 produce IFN- following LPS
challenge. In contrast, frequencies of IFN- producers among
CD3-NK1- and
CD3+NK1- cells were low.
The higher intensity of IFN- staining among
CD3-NK1+ cells compared
with other cell populations suggests that NK cells were major IFN-
producers in J281-/- mice following LPS
challenge. The proportion of
CD3+NK1+ cells was markedly
lower in the liver of J281-/- mice than in
C57BL/6 mice (Fig. 2; Table II). Similarly to
2m-/- mice, the
proportion of CD3-NK1+
cells was increased in the liver of J281-/-
mice compared with C57BL/6 mice (Fig. 2; Table II). Our results show
that NK1+ cells are the major source of IFN-
in J281-/- mice following LPS challenge.
Mice deficient for V14+NKT cells are susceptible to
the lethal shock in the generalized Shwartzman reaction
We examined whether V14+NKT cells are
involved in the lethal shock in the generalized Shwartzman reaction. In
contrast to previous findings (31), the susceptibility to
the lethal shock in the generalized Shwartzman reaction was slightly
higher in J281-/- than in
J281+/- mice (Table IV). Similarly,
2m-/- mice were more
susceptible to the shock than C57BL/6 mice (data not shown).
J281-/- mice were rescued by
NK1+ cell depletion from the lethal shock with
125 or 150 µg LPS (Table IV). These results argue against a critical
contribution of V14+NKT cells in the
generalized Shwartzman reaction.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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14+NKT cells play a critical role in
LPS-induced shock of mice.
2m-/- mice, which are
devoid of V14+NKT cells but not of NK cells,
were more susceptible to LPS-induced lethal shock than WT mice, and in
vivo depletion of NK1+ cells prevented
2m-/-, as well as WT,
mice from succumbing to the lethal effects of LPS. Moreover,
J281-/- mice exclusively lacking
V14+NKT cells were slightly more susceptible
to LPS-induced lethal shock than their
J281+/- littermates and were rescued from
lethal effects of LPS by NK1+ cell depletion.
It is generally accepted that TNF- secreted by macrophages is a
pivotal mediator of the cytokine cascade that leads to LPS-induced
shock (1, 2, 3, 4). However, serum levels of TNF- were
comparable in 2m-/-
and WT mice, although
2m-/- mice were more
susceptible to LPS-induced shock than WT mice. Serum levels of IFN-
were significantly higher in
2m-/- mice than in WT
mice, and endogenous IFN- neutralization rescued
2m-/- mice as well as
WT mice from lethal shock. NK1+ cell depletion
significantly, though not completely, reduced serum levels of IFN-
in 2m-/- mice
following LPS challenge, and high frequencies of IFN- producers were
detected among NK cells in
2m-/- mice following
LPS challenge. Our results suggest that NK cells are a major source of
IFN- in LPS-induced shock, which is consistent with recent findings
showing a central role of NK cells in IFN- production in endotoxemia
(36). Because considerable numbers of IFN- producers
were detected among V14+NKT cells in WT mice,
we cannot exclude the contribution of V14+NKT
cells in normal mice. Yet, our data exclude a pivotal role of
V14+NKT cells, because IFN--producing
activity was markedly higher in NK cells than in
V14+NKT cells.
IL-4 is involved in anti-inflammatory responses and
V14+NKT cells are potent IL-4 producers
(12, 14, 19, 20, 21). This raises the possibility that
V14+NKT cells participate in prevention of
LPS-induced lethal shock (37). It is conceivable that
V14+NKT cells play a dual, antagonistic role
in septic shock: they could promote shock via IFN- and prevent it
via IL-4. Experimental conditions could then determine which cytokine
dominates and, as corollary, which function prevails. In our study,
susceptibility of C57BL/6 mice to LPS-induced lethal shock was
virtually unaffected by endogenous IL-4 neutralization. These
findings argue against increased susceptibility of
2m-/- and
J281-/- mice to shock being caused by
deficient IL-4 production.
In addition to V14+NKT cells, various
2m-independent NKT cells have been described
(38, 39, 40, 41, 42). We found that
2m-independent NKT cells are potent IFN-
producers (41, 42). Indeed, considerable numbers of
IFN--producing NKT cells were detected in
2m-/- mice following
LPS challenge. Therefore, we do not exclude contribution of
2m-independent NKT cells to LPS-induced
shock. However, we consider a major contribution of NK cells,
because 1) absolute numbers of NK cells markedly exceeded those of
unconventional NKT cells, and 2) IFN--producing activities were
markedly higher in NK cells than in unconventional NKT cells.
Substantial numbers of IFN- producers were also identified among
CD3+NK1- cells in
2m-/- mice, indicating
IFN- production by 2m-independent T cells
following LPS challenge. Consistent with this, depletion of
NK1+ cells did not completely rescue
2m-/- mice from lethal
shock, and IFN- was detectable in sera of NK1+
cell-depleted 2m-/-
mice following LPS challenge. Hence, IFN--secreting cells other than
NK1+ cells must contribute to the lethal effects
of LPS. Because 2m-/-
mice are devoid of conventional CD8+ T cells, it
is possible that conventional CD4+ T cells
produce IFN- in response to LPS. We consider it likely that these
conventional CD4+ T cells play a minor role,
because susceptibility to LPS-induced shock was virtually unchanged in
A-/- mice which lack conventional
CD4+ T cells (Y. Emoto, unpublished observation).
Hence, the precise nature of the
CD3+NK1- cells requires
further characterization.
Interactions of NK and V14+NKT cells have been
described in different experimental systems (43, 44).
These studies revealed an essential role of
V14+NKT cells in NK cell activation. Yet, NK
cells were highly activated after LPS challenge in
2m-/- mice. These
results argue against an essential role of
V14+NKT cells in LPS-induced activation of NK
cells. Under normal conditions interactions with
V14+NKT cells cannot be excluded, because our
experiments revealed reduced IFN- production by NK cells in
J281-/- mice following LPS challenge. Thus,
we assume that septic shock is not caused by a single cell type, and
that different cell populations participate in septic shock in a
hierarchical manner.
In the study of Dieli et al. (31),
J281-/- mice were found to be more resistant
to LPS-induced lethal shock than C57BL/6 mice. In contrast, we observed
that J281-/- mice were not more resistant to
lethal shock than their J281+/- littermates.
We cannot provide an appropriate explanation for this discrepancy at
present. However, it is possible that the susceptibility to LPS-induced
shock is influenced by the genetic background. Indeed, in our study,
J281+/- mice as well as 129 mice crossed onto
C57BL/6 were more resistant to LPS-induced lethal shock than C57BL/6
mice (Y. Emoto, unpublished observation). In addition, an influence of
body weight on resistance to LPS-induced shock is possible. We find
that the body weight of J281-/- mice, in
particular of male mice, is significantly higher (1.5-fold) than
that of age-matched C57BL/6 mice (Y. Emoto, unpublished observation).
The generalized Shwartzman reaction describes a lethal shock syndrome
which is induced by consecutive challenge with low doses of LPS.
Locally injected LPS causes IFN- production by
NK1+ cells which in turn primes macrophages
(27, 28). Upon subsequent exposure to LPS, primed
macrophages produce large amounts of TNF-, which results in acute
lethal shock (27, 28). V14+NKT
cells have recently been claimed to play a central role in the
pathogenesis of the generalized Shwartzman reaction (29, 31). In contrast, in our experiments
2m-/- mice were more
susceptible to lethal consequences of the generalized Shwartzman
reaction than WT mice, and J281-/- mice were
more susceptible than J281+/- mice. Our
results argue against a critical role of
V14+NKT cells in the generalized Shwartzman
reaction, although the discrepancy might be due to the use of different
experimental systems. Because recent studies suggest that NK cells do
not participate in the pathogenesis of the generalized Shwartzman
reaction (36), we consider it is possible that NKT cells
other than V14+NKT cells participate in this
reaction.
In conclusion, we describe a critical role of NK rather than
V14+NKT cells in the pathogenesis of
LPS-induced shock. Using NK cell-deficient mice, evidence against a
critical role of NK cells in the generalized Shwartzman reaction has
been provided (36). In contrast, evidence for a critical
role of V14+NKT cells in LPS-induced lethal
shock has also been obtained (31). Therefore, it is
tempting to assume that LPS-induced shock is caused by different cell
populations which contribute to shock in a hierarchical order.
Depending on the shock model used and the type of knockout mice used
for analysis, the importance of distinct cell populations for pathology
seems to vary and in the systems analyzed in this study NK cells were
of major importance. Our data also emphasize the notion that
observations obtained with gene-disruption mutants must be carefully
interpreted.
|
Acknowledgments |
|---|
281-/- mice. We are grateful to M. Stäber for
mAb purification, K. Bordasch for screening of mice, and L.
Lom-Terborg for proofreading this manuscript. |
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Masashi Emoto, Department of Immunology, Max-Planck-Institute for Infection Biology, Schumannstrasse 21/22, 10117 Berlin, Germany. E-mail address: emoto{at}mpiib-berlin.mpg.de
3 Abbreviations used in this paper: 2m, 2-microglobulin; WT, wild type; LMNC, liver mononuclear cells; SA, streptavidin.
Received for publication February 28, 2002. Accepted for publication May 30, 2002.
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N. A. Nagarajan and M. Kronenberg Invariant NKT Cells Amplify the Innate Immune Response to Lipopolysaccharide J. Immunol., March 1, 2007; 178(5): 2706 - 2713. [Abstract] [Full Text] [PDF]
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 R. Plaza, J. L. Rodriguez-Sanchez, and C. Juarez Staphylococcal Enterotoxin B In Vivo Modulates both Gamma Interferon Receptor Expression and Ligand-Induced Activation of Signal Transducer and Activator of Transcription 1 in T Cells Infect. Immun., January 1, 2007; 75(1): 306 - 313. [Abstract] [Full Text] [PDF]
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J. Liu, G. Mankani, X. Shi, M. Meyer, S. Cunningham-Runddles, X. Ma, and Z. S. Sun The circadian clock period 2 gene regulates gamma interferon production of NK cells in host response to lipopolysaccharide-induced endotoxic shock. Infect. Immun., August 1, 2006; 74(8): 4750 - 4756. [Abstract] [Full Text] [PDF]
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 V. T. Enoh, C. D. Fairchild, C. Y. Lin, T. K. Varma, and E. R. Sherwood Differential effect of imipenem treatment on wild-type and NK cell-deficient CD8 knockout mice during acute intra-abdominal injury Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R685 - R693. [Abstract] [Full Text] [PDF]
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 V. T. Enoh, C. Y. Lin, T. K. Varma, and E. R. Sherwood Differential effect of imipenem treatment on injury caused by cecal ligation and puncture in wild-type and NK cell-deficient {beta}2-microgloblin knockout mice Am J Physiol Gastrointest Liver Physiol, February 1, 2006; 290(2): G277 - G284. [Abstract] [Full Text] [PDF]
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 H. Ito, N. Koide, A. Morikawa, F. Hassan, S. Islam, G. Tumurkhuu, I. Mori, T. Yoshida, S. Kakumu, H. Moriwaki, et al. Augmentation of lipopolysaccharide-induced nitric oxide production by {alpha}-galactosylceramide in mouse peritoneal cells Innate Immunity, August 1, 2005; 11(4): 213 - 219. [Abstract] [PDF]
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 J. G. Maresh, H. Xu, N. Jiang, and R. V. Shohet In Vivo Transcriptional Response of Cardiac Endothelium to Lipopolysaccharide Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1836 - 1841. [Abstract] [Full Text] [PDF]
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D. S. Vinay, B. K. Choi, J. S. Bae, W. Y. Kim, B. M. Gebhardt, and B. S. Kwon CD137-Deficient Mice Have Reduced NK/NKT Cell Numbers and Function, Are Resistant to Lipopolysaccharide-Induced Shock Syndromes, and Have Lower IL-4 Responses J. Immunol., September 15, 2004; 173(6): 4218 - 4229. [Abstract] [Full Text] [PDF]
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