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Department of Immunology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production were more strongly suppressed in BALB/c macrophages
than in C57BL/6 macrophages. When macrophages were treated with
indomethacin or EP4 antagonist, Th1 cytokines were more markedly
increased in cells from BALB/c mice than in those from C57BL/6 mice.
Although cyclooxygenase-2 was expressed similarly after LPS stimulation
in these mouse strains, the release of arachidonic acid and the
expression of type V secretory phospholipase A2 mRNA were
greater in BALB/c macrophages. However, exogenous addition of
arachidonic acid did not reverse the lower production of
PGE2 by C57BL/6 macrophages. The expression of microsomal
PGE synthase, a final enzyme of PGE2 synthesis, was also
greater in BALB/c macrophages. These results indicate that the greater
production of PGE2 by macrophages, which is regulated by
secretory phospholipase A2 and microsomal PGE synthase but
not by cyclooxygenase-2, is related to the suppression of Th1 cytokine
production in BALB/c mice. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production by T cells (13, 14). In
B cell function, PGE2 enhances IgE production of
IL-4- and LPS-stimulated B cells in vitro (15). Recently,
we reported that PGE2 preferentially enhances
Th2-type chemokine, macrophage-derived chemokine (CC chemokine ligand
22), production by APCs (16). These reports show
that the effects of PGE2 almost suppress
Th1-related immune responses and augment Th2-related immune responses,
which is similar to the function of IL-4 in immune responses. PGE2 is synthesized by three sequential steps (17). First, arachidonic acid is liberated from membrane phospholipids by the action of cytosolic phospholipase A2 (PLA23; cPLA2) or secretory PLA2 (sPLA2) isozymes. Next, released arachidonic acid is converted to PGH2 by two cyclooxygenase (COX) isoforms, COX-1 and COX-2. Finally, PGH2 is converted to PGE2 by cytosolic PGE synthase (cPGES) and microsomal PGE synthase (mPGES) (18, 19). Each enzyme is important for the biosynthesis of PGE2 in various cells.
Genetic background is also important in the balance of Th1/Th2
differentiation in mice (20, 21, 22, 23). In general, BALB/c mice
easily induce Th2 responses after infection or immunization, such as
Leishmania major (24, 25, 26). One of the
mechanisms to induce Th2 response in BALB/c mice is the participation
of IL-4, which is rapidly and abundantly produced by L.
major infection and induces selective loss of IL-12R expression
and IFN- production (27, 28, 29, 30, 31, 32). However, APCs such as
dendritic cells and macrophages also influence Th differentiation by
producing IL-12 and IFN-. Previously, we reported that splenic APCs
from BALB/c mice have a greater sensitivity to the suppressive effect
of PGE2 (14). Furthermore, we showed
that the expressions of STAT4 and IFN- were reduced in macrophages
from BALB/c mice (33). These results suggest that
macrophages play an important role in the strain difference in Th1/Th2
activation.
In this study, we show evidence that macrophages from BALB/c mice
produce greater amount of PGE2 than ones from any
other strain of mice. PGE2 from BALB/c
macrophages strongly suppress the production of IL-12 from macrophages
themselves and of IFN- from T cells. The strain difference in
PGE2 production by macrophages is due to a
differential expression of sPLA2 and mPGES,
initial and terminal enzymes of arachidonate cascade, respectively, but
not of COX-2. These results suggest that sPLA2
and mPGES are novel therapeutic targets in the control of Th1/Th2
activation and Th2-related diseases.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female A/J, AKR/N, BALB/c, CBA/N, C3H/HeN, C57BL/6, and DBA/2 mice (7–8 wk old) were purchased from Japan SLC (Shizuoka, Japan) or Charles River Japan (Yokohama, Japan). These mice were maintained in the Laboratory Animal Research Center at the University of Occupational and Environmental Health under specific pathogen-free conditions. All animal experiments were performed according to the guidelines for the care and use of animals approved by the University of Occupational and Environmental Health.
Reagents
PGE2, indomethacin, arachidonic acid, anti-COX-1 Ab, anti-COX-2 Ab, anti-mPGES Ab, and anti-cPGES Ab were purchased from Cayman Chemicals (Ann Arbor, MI). Anti-CD3 Ab was purchased from BioSource International (Camarillo, CA). [5,6,8,9,11,12,14,15-3H]Arachidonic acid (sp. act. 200 Ci/mmol) and HRP-conjugated anti-rabbit Ig were purchased from Amersham Biosciences (Uppsala, Sweden). LPS (Escherichia coli serotype 055:B5) was purchased from Sigma-Aldrich (St. Louis, MO). EP4 antagonist (L-161982) was kindly donated by Dr. R. Young (Merck Frosst, Quebec, Canada) (34, 35).
Preparation of cells
Peritoneal exudate cells were harvested 3 days after i.p. injection of 2 ml of 4% thioglycolate broth (Eiken, Tokyo, Japan), and cultured in an RPMI 1640 medium (Nissui Pharmaceutical, Tokyo, Japan) supplemented with 10% FBS (BioWhittaker, Walkersville, MD), 2 mM glutamine, 50 U/ml penicillin, and 50 µg/ml streptomycin (all from Life Technologies, Rockville, MD) at 37°C for 2 h. Nonadherent cells were vigorously washed off with warm HBSS four times, and adherent cells were used as macrophages. The purity of macrophages was >95% F4/80 and Mac-1 positive as determined by flow cytometry. CD4+ T cells were purified from spleen cells by MACS (Miltenyi Biotec, Bergisch-Gladbach, Germany) according to the manufacturer’s procedures, and the purity of cells was >95% CD4+ cells. Mac-1+ cells from spleen cells were sorted by MACS, and used as splenic macrophages, whose purity was >90%.
In vitro stimulation of cells
Peritoneal macrophages (5 x
105/ml/well) and splenic macrophages (1 x
106/ml/well) from several strains of mouse were
seeded into 24-well plates (Falcon 3047; BD Biosciences, Franklin
Lakes, NJ). Cells were pretreated with or without indomethacin (1 µM)
or EP4 antagonist (0.1
10 µM) for 5 h, and then stimulated
with LPS (1 µg/ml) for an additional 24 h. Cell-free culture
supernatants were collected and used for cytokine or
PGE2 assay as described below. In some
experiments, arachidonic acid (0.330 µM) was added at the time of
LPS stimulation. For Western blotting and mRNA analysis, macrophages
(4 x 106/3 ml/well) from BALB/c and C57BL/6
mice were seeded into 6-well plates (Falcon 3046). Cells were
stimulated with LPS for 6–18 h, and used for the assay of Western
blotting and RT-PCR as described below. For the assay of T-macrophage
interaction, macrophages (1 x 105/250
µl/well) from BALB/c and C57BL/6 mice were seeded in 48-well plates
(Falcon 3078), and treated with or without 1 µM of indomethacin or
EP4 antagonist for 5 h. After treatments,
CD4+ T cells from C3H/HeN mice (1 x
106/250 µl/well) were added to each well, and
stimulated with LPS (1 µg/ml), anti-CD3 Ab (1 µg/ml), or LPS
plus anti-CD3 Ab for an additional 24 h. Cell-free
supernatants were collected, and used for IFN- assay as described
below.
mRNA analysis
mRNA expression was detected by RT-PCR as described previously
(33). The sequence of the sense and antisense primers,
product size, and the number of PCR cycles were as follows: 
-actin,
5'-ACCAACTGGGACGACATGGAGAA-3' and 5'-GTGGTGGTGAAGCTGTAGCC-3', 380
bp, 22 cycles; EP4, 5'-CGTAGTATTGTGCAAGTCGC-3' and
5'-GGCGATGAGTAAGATGACCA-3', 388 bp, 34 cycles;
sPLA2 type IIA, 5'-CAGTTTGGGGAAATGATTCGGC-3' and
5'-GAAACATTCAGCGGCGGCTTTA-3', 289 bp, 36 cycles;
sPLA2 type V, 5'-CAGGGGGCTTGCTAGAACTCAA-3'
and 5'-AAGAGGGTTGTAAGTCCAGAGG-3', 329 bp, 30 cycles; and
cPLA2, 5'-TGTTCAACAGAGTTTTGG-3' and
5'-AACAGAGCAACGAGATGG-3', 983 bp, 34 cycles. PCR conditions of
-actin, EP4, and cPLA2 were 94°C for 1 min,
55°C for 1 min, and 72°C for 2 min, and those of
sPLA2 type IIA and sPLA2
type V were 94°C for 1 min, 58°C for 1 min, and 72°C for 1 min
and 20 s. Each cycle is four or five cycles below the maximum
amplification, which is the linear part of the increase of PCR
products, as determined by a preliminary experiment.
Cytokine and PGE2 assay
IFN- was determined by a standard ELISA as described
previously (14). TNF was determined by cytotoxic assay
using L929 cells by the method of Flick and Gifford (36).
IL-12p70 was measured using Cytoscreen immunoassay (BioSource
International) according to the manufacturer’s protocol.
PGE2 was measured using
STAT-PGE2 enzyme immunoassay kit (Cayman
Chemicals) according to the manufacturer’s protocol.
Western blot analysis
Cells were lysed on ice with 100 µl of Laemmli sample buffer solution. Obtained samples were boiled for 5 min, electrophoresed by 7% (for COX-2) or 15% (for cPGES and mPGES) SDS-PAGE, transferred to polyvinylidene difluoride membrane (Bio-Rad, Hercules, CA), and blotted with anti-COX-2, anti-cPGES, or anti-mPGES Ab (1/1000), and HRP-conjugated secondary Ab (1/2000). The reactive bands were visualized with Lumi-LightPLUS Western blotting substrate (Roche Diagnostics, Indianapolis, IN) as a substrate and Fluorochem (Alpha Innotech, San Leandro, CA) as a detector. For the assessment of protein concentrations of samples, cells were lysed with Nonidet P-40 lysis buffer (20 mM Tris-HCl (pH 7.5), 150 mM NaCl, and 1% Nonidet P-40). Protein concentrations were determined by a Bio-Rad protein assay standardized with BSA.
Arachidonic acid release
Macrophages were seeded into a 24-well plate at 2.5 x 105/400 µl/well in an RPMI containing 2% FBS, and labeled with [3H]arachidonic acid (1 µCi/ml) for 4 h. After washing four times, the medium was replaced with 250 µl of fresh medium, and the cells were cultured in the presence or absence of LPS for 5 h. Then, 125 µl of culture supernatants were collected, and the amount of released arachidonic acid was measured by a scintillation counter (Aloka, Tokyo, Japan). Remaining cells were lysed with 250 µl of 1% Triton X-100, and the radioactivities of lysed cells were measured for the total radioactivity incorporated. The amount of arachidonic acid release was expressed as the percentage of release, which was calculated as follows: percentage of release of arachidonic acid = ((released radioactivity)/(released radioactivity + total radioactivity incorporated)) x 100.
Statistical analysis
All experiments were repeated at least three times, and some representative results are shown in figures. Statistical analyses were performed between BALB/c and C57BL/6 mice using Student’s t test. A confidence level of <0.05 was considered significant (37).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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At first, we investigated the capacity of PGE2 production by macrophages from several mouse strains. After LPS stimulation, macrophages from BALB/c mice produced greater amounts of PGE2 than cells from other mouse strains (Fig. 1A). Because C57BL/6 and BALB/c mice are important strains as the representative Th1- and Th2-dominant mice, respectively, we compared mainly these two strains in the following experiments. We performed the same experiment using splenic macrophages and found that splenic macrophages from BALB/c mice also produced greater amounts of PGE2 (Fig. 1B). These phenomena were not restricted to LPS stimulation, because similar results were obtained in Staphylococcus aureus Cowan I-stimulated macrophages from BALB/c and C57BL/6 mice (data not shown). These results indicate that PGE2 production is augmented in BALB/c macrophages as compared with C57BL/6 macrophages.
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To study the role of PGE2 produced by macrophages, first we assessed the capacity of Th1 cytokine production by macrophages from BALB/c and C57BL/6 mice. When macrophages were treated with indomethacin, a COX inhibitor, and stimulated with LPS, IL-12 and TNF productions were markedly increased in BALB/c macrophages, while only weak responses were observed in C57BL/6 macrophages (Fig. 2). Because it has been reported that the suppressive effect of Th1 cytokine by PGE2 in macrophages is mainly mediated by the EP4 receptor (38), we performed the same experiments using an EP4 antagonist and obtained similar results, that is, EP4 antagonist significantly augmented IL-12 and TNF production in macrophages from BALB/c mice, but not in ones from C57BL/6 mice (Fig. 2). We also assessed EP4 mRNA expression in macrophages by RT-PCR, and macrophages from both strains similarly expressed EP4 mRNA (Fig. 3). The treatment with EP4 antagonist had no effect on PGE2 production by macrophages (data not shown).
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production by T
cells. Macrophages from BALB/c or C57BL/6 mice were cultured in the
presence or absence of indomethacin or EP4 antagonist, and then
allogenic CD4+ T cells (from C3H/HeN mice) were
added and stimulated with LPS, anti-CD3 Ab, or LPS plus
anti-CD3 Ab. As shown in Fig. 4, indomethacin- or EP4 antagonist-treated macrophages significantly
enhanced T cell-derived IFN- production after LPS- or LPS plus
anti-CD3 Ab-stimulation as compared with nontreated macrophages.
The degree of enhancement of IFN- production is much stronger in
macrophages from BALB/c mice, and only weak effects were observed in
macrophages from C57BL/6 mice. T cells or macrophages alone did not
produce detectable levels of IFN- even after stimulation (data not
shown). These results indicate that macrophage-derived
PGE2 has a suppressive effect on Th1 cytokine
production by macrophages as an autocrine mechanism, and on IFN-
production by T cells as a paracrine mechanism. The autocrine and
paracrine mechanisms of macrophage-dependent suppression were much
stronger in BALB/c mice, corresponding to the amount of
PGE2.
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It is known that COX-2 expression is closely linked with PGE2 production in several cell types. We examined whether COX-2 expression in macrophages was different between BALB/c and C57BL/6 mice. As shown in Fig. 5, COX-2 protein was not expressed in nonstimulated macrophages, and those expressions were equally augmented after LPS stimulation in macrophages from both mouse strains. This result indicates that the enhanced production of PGE2 by BALB/c macrophages is not due to the difference in COX-2 expression.
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It is known that arachidonic acid is a substrate for prostanoid synthesis, and the regulation of release of arachidonic acid is an initial step of the arachidonate cascade. We examined whether the release of arachidonic acid in macrophages was different between BALB/c and C57BL/6 mice. When cells were labeled with [3H]arachidonic acid, radioactivities of incorporated arachidonic acid were almost the same between BALB/c and C57BL/6 macrophages. However, the release of arachidonic acid from macrophages was different. Macrophages spontaneously released arachidonic acid, and the release increased after LPS stimulation. Both spontaneous and LPS-induced release of arachidonic acid were greater in BALB/c macrophages than in C57BL/6 ones (Table I).
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Next, we assessed whether the enhanced production of PGE2 was due to the difference in the amount of released arachidonic acid in BALB/c macrophages. Macrophages from BALB/c and C57BL/6 mice were stimulated with LPS in the presence or absence of a large amount of arachidonic acid. The addition of arachidonic acid induced overproduction of PGE2, and IL-12 production was suppressed in a dose-dependent manner, corresponding to the amount of PGE2 (Fig. 7). However, contrary to our expectations, macrophages from BALB/c mice further produced greater amounts of PGE2 with the addition of an excess amount (30 µM) of arachidonic acid, and C57BL/6 mice did not reach the level of BALB/c mice. These results suggest that not only the greater release of arachidonic acid but also other factors relate to the enhanced production of PGE2 in BALB/c macrophages.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PGE2 suppresses Th1 responses and consequently activates Th2 responses at various steps. Representative effects of PGE2 in the immune responses are 1) a selective suppression of cytokine production by Th1 and an inhibition of Th1 differentiation (8, 9), 2) a suppression of Th1-activating cytokine production by APCs (11, 12), and 3) an enhanced production of IgE by B cells (15). In a previous report, we found that PGE2 up-regulated Th2-type chemokine production but suppressed Th1-type chemokine production by APCs (16), and indicated that PGE2 played a role in the determination of the Th1/Th2 balance at both the induction and effector phases of the immune response by modulating cytokine and chemokine production. Furthermore, we reported that BALB/c spleen cells had a greater sensitivity to the suppressive effect of PGE2, while there was no significant difference in PGE2 production by spleen cells from BALB/c, C3H/HeN, and C57BL/6 mice (14). We used whole spleen cells in our previous experiments. However, we used highly purified macrophages in this study. The differences in the amount of PGE2 produced seem to depend on the purity of participating cells, and macrophages from BALB/c mice have a capacity to produce a greater amount of PGE2 than cells from C57BL/6 mice (Fig. 1).
Not only COX but also several other molecules participate in PGE2 synthesis. We found the enhanced expression of sPLA2 type V and mPGES in BALB/c macrophages (Figs. 6 and 8). In general, the expression level of COX has been the focus of PGE2 synthesis. However, the regulation or the cooperation of all these enzymes is important in PGE2 biosynthesis. In our study, macrophages from BALB/c and C57BL/6 mice expressed similar levels of COX-2 protein (Fig. 5). In fact, there are many reports that most tumor cells overexpressed COX-2 (50). However, we found that not all tumor cells expressed COX-2 to produce PGE2 (data not shown). The first step of PGE2 synthesis is the liberation of arachidonic acid from the membrane phospholipids by PLA2. Especially cPLA2, sPLA2 type IIA, and sPLA2 type V play a pivotal role in the release of arachidonic acid as reported by several investigators (39, 40, 41, 42, 43, 44). In our experiments, macrophages did not express sPLA2 type IIA, and they expressed more sPLA2 type V in BALB/c macrophages than in C57BL/6 macrophages (Fig. 6). Balboa et al. (39) and Reddy et al. (51) reported that macrophage cell lines and cultured mast cells expressed only sPLA2 type V, which was related to the release of arachidonic acid. These reports are consistent with our study, and we suggest that the regulation of sPLA2 type V expression is important in the release of arachidonic acid. PGES is a terminal enzyme of PGE2 biosynthesis, and two isoforms of PGES have been reported: cPGES, which is constitutively expressed like COX-1, and mPGES, which is inducible. We also obtained the same results showing that cPGES is constitutive and mPGES is inducible, and the strain differences were observed in mPGES expression, but not in cPGES expression (Fig. 8). These results indicate that the enhanced production of PGE2 in BALB/c macrophages is due to the greater expression of sPLA2 type V and mPGES, but not of COX-2. We suggest that sPLA2 type V and mPGES are novel therapeutic targets for the regulation of PGE2 production in allergic diseases.
It is known that one of the mechanisms of Th2 activation by
PGE2 depends on the intracellular accumulation of
cAMP (17). There are four major PGE2
receptor subtypes of G protein-linked receptor families called EP1,
EP2, EP3, and EP4, and, of these, EP2 and EP4 receptors are coupled to
adenylate cyclase (17). A recent report indicated that EP4
was mainly related to the suppression of Th1 cytokines in macrophages,
and EP2 was linked to the T cell activation (38). We found
that EP4 antagonist strongly increased IL-12 and TNF production by
macrophages from BALB/c mice but not by those from C57BL/6 mice,
similar to the effects of treatment with a COX inhibitor, indomethacin
(Fig. 2). These results indicate that PGE2
produced by macrophages suppresses IL-12 and TNF production via the EP4
receptor in an autocrine manner (Fig. 2). Moreover, we also found that
macrophages treated with an EP4 antagonist enhanced T cell-derived
IFN- production by interfering with the paracrine suppression of
PGE2 (Fig. 4). Thus, the EP4 antagonist works as
an effective enhancer of Th1 activation by modulating
macrophage-derived IL-12 production. Now, we are investigating the
manipulation of the Th1/Th2 balance using EP4 antagonist in
vivo.
There are also several reports that PGE2
production is enhanced in Th2-related diseases. Monocytes from patients
with atopic dermatitis produce a greater amount of
PGE2 than cells from normal donors, and the
addition of COX inhibitor reverses the suppressive effect of IFN- by
PGE2 produced from PBMC (52, 53). In
a murine model of allergic airway inflammation, a greater amount of
PGE2 is detected in the bronchoalveolar lavage
fluid (54). In Leishmania infection, cells from
infected mice produce more PGE2 in BALB/c mice
than in C57BL/6 mice, and the expression of COX-2 is observed in BALB/c
mice, but not in C57BL/6 mice (55, 56). In a murine model
of endotoxin liver injury, PGE1 acts as a
protective factor by inducing Th2 responses (57). These
reports indicate that PGE2 plays an important
role in the control of diseases by regulating Th1/Th2 balance.
Therefore, we suggest that the modulation of
PLA2, COX, and PGES, or receptor antagonists for
PGE2, are promising therapeutic targets for
several diseases.
In conclusion, we found that macrophages from BALB/c mice produced
greater amounts of PGE2 than cells from other
strains of mice. The greater amount of PGE2
produced by BALB/c macrophages strongly suppressed macrophage-derived
IL-12 and T cell-derived IFN- production by autocrine and paracrine
manners, and induced Th2-dominant immune responses. The increased
production of PGE2 by BALB/c macrophages is due
to the greater expression of sPLA2 type V and
mPGES, but not COX-2. Thus, macrophages from Th2-dominant BALB/c mice
have different functional characters regarding
PGE2 production as compared with other strains of
mice. We previously reported the reduced expression of STAT4 and
IFN- in macrophages from BALB/c mice. Taking these studies together,
we propose that the altered macrophage functions affect Th1/Th2
balance, and the modulation of macrophage functions will open a new way
for the treatment of immunological diseases, such as autoimmune or
allergic diseases.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Etsushi Kuroda, Department of Immunology, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. E-mail address: kuroetu{at}med.uoeh-u.ac.jp
3 Abbreviations used in this paper: PLA2, phospholipase A2; cPLA2, cytosolic PLA2; sPLA2, secretory PLA2; COX, cyclooxygenase; cPGES, cytosolic PGE synthase; mPGES, microsomal PGE synthase.
Received for publication August 21, 2002. Accepted for publication November 12, 2002.
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References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and IL-2, but not IL-4 and IL-5. J. Immunol. 155:4604.[Abstract]
level of activated human CD4+ T cells. J. Immunol. 156:1722.[Abstract]
-interferon. Infect. Immun. 62:2590. in modulation of immunity to Borrelia burgdorferi in mice. J. Immunol. 155:2020.[Abstract]
modulates the early development of Th1 and Th2 responses in a murine model of cutaneous leishmaniasis. J. Immunol. 147:3149.[Abstract]
4V
8 CD4+ T cells instructs Th2 development and susceptibility to Leishmania major in BALB/c mice. Immunity 6:541.[Medline]
8.2+CD4+CD62L-CD45RB- T cells in non-MHC gene-controlled predisposition toward skewing into T helper type-2 immunity in BALB/c mice. J. Immunol. 158:5698.[Abstract]
2-chain expression on CD4+ T cells resulting in a state of unresponsiveness to IL-12. J. Immunol. 161:6159.
in macrophages from BALB/c mice. J. Immunol. 168:5477.This article has been cited by other articles:
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|
 |
|
 H. Kitamura, M. Ito, T. Yuasa, C. Kikuguchi, A. Hijikata, M. Takayama, Y. Kimura, R. Yokoyama, T. Kaji, and O. Ohara Genome-wide identification and characterization of transcripts translationally regulated by bacterial lipopolysaccharide in macrophage-like J774.1 cells Physiol Genomics, October 8, 2008; 33(1): 121 - 132. [Abstract] [Full Text] [PDF]
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 K. Okunishi, M. Dohi, K. Fujio, K. Nakagome, Y. Tabata, T. Okasora, M. Seki, M. Shibuya, M. Imamura, H. Harada, et al. Hepatocyte Growth Factor Significantly Suppresses Collagen-Induced Arthritis in Mice J. Immunol., October 15, 2007; 179(8): 5504 - 5513. [Abstract] [Full Text] [PDF]
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 |
|
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Y. Shibata, A. Nishiyama, H. Ohata, J. Gabbard, Q. N. Myrvik, and R. A. Henriksen Differential effects of IL-10 on prostaglandin H synthase-2 expression and prostaglandin E2 biosynthesis between spleen and bone marrow macrophages J. Leukoc. Biol., April 1, 2005; 77(4): 544 - 551. [Abstract] [Full Text] [PDF]
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suppressed from the group of LPS stimulation alone. A.A., Arachidonic
acid.