| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Departments of
* Pharmacology,
Gastroenterological Surgery, Transplant, and Surgical Oncology, and
Pathology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-inducing factor (1).
IL-18 requires the cleavage at its aspartic acid residue by
IL-1
-converting enzyme/caspase-1 to become the active, mature
protein (2, 3). APCs produce IL-18 during interactions
with cognate T cells (4). IL-18 plays a role in the
expression of Th1 responses (1, 5, 6). In an established
Th1 clone, the levels of IFN- induced by IL-18 were higher than
those induced by IL-12 (1). IL-18 acts in synergy with
IL-12 to induce IFN- production in CD4+ cells
by using different signaling pathways (5, 7), and both
IL-12 and IL-18 are necessary for the full expression of Th1 responses.
However, at early stages of T cell differentiation, IL-18 can promote
either Th1 or Th2 responses, dependent on IL-12 or IL-4
(8). IL-18 enhances T cell and NK cell cytotoxicity and
directly induces IFN- production by NK cells (6). The
function of IL-18 is suggested to be functionally regulated by IL-18
binding protein, a recently described Ig-like binding factor that
strongly suppresses the development of Th1 responses through IL-18
neutralization (9). The acquired immune response requires the engagement of T cells with APC, mediated by interaction of the TCR with antigenic peptides presented by MHC molecules on the APC (10). These recognition and signaling events just described are now known to be effected by a dynamic structure known as the immunological synapse, which is assembled upon T cell-APC contact (11, 12). For T cell activation, the costimulatory signals are required from accessory receptors (13); the interaction of LFA-1 (CD11a/CD18) with its ligand, ICAM-1/CD54, and the binding of CD28 to B7 (B7.1/CD80 or B7.2/CD86) play important roles in cell signaling as well as cell-cell adhesion. The binding of CD28 on the T cell surface to B7 present on APC determines the direction of T cell responses, activation or anergy, after antigenic stimulation (14, 15). The interaction of LFA-1 with ICAM-1 is important in the activation of T cells by lowering the concentration of Ag required for stimulation of T cells and promoting sustained signaling from the TCR in a CD28-independent manner (16, 17).
Recently, we found that IL-18 up-regulated the expression of ICAM-1 in
a monocyte population in human PBMC as well as KG-1, a human
myelomonocytic cell line, while the expression of CD11a, CD18, CD29,
CD44, and CD62 ligand in monocytes and that of ICAM-1, CD11a, CD18,
CD29, CD44, and CD62 ligand in T cells were not influenced by IL-18
(18, 19). IL-18 in the same concentration range stimulated
the production of IL-12, TNF-
, and IFN- in cultures of human
PBMC. However, IL-18-induced expression of ICAM-1 in monocytes was
independent of IL-18-elicited IL-12, TNF-, and IFN- production
(18). Anti-ICAM-1 and anti-LFA-1 Abs not only
prevented IL-18-induced aggregation of PBMC, but also down-regulated
IL-18-induced production of IL-12, IFN-, and TNF-
(18). These findings strongly indicated that the
ICAM-1/LFA-1 interaction induced by IL-18 is important for the enhanced
cytokine induction. However, little is known about the effect of IL-18
on the expression of other costimulatory molecules, such as B7.1 and
B7.2, on monocytes, although these costimulatory molecules are
intimately involved in IL-2 production and clonal expansion in T cell
during Ag presentation (20, 21). Some cytokines that
induce Th1/Th2 immune responses exert differential effects on B7
isoform expression on resting monocytes (22). IL-4 and
IL-10 down-regulated B7.2 and moderately up-regulated B7.1 expression.
IFN- enhanced the expression of both B7.1 and B7.2 isoforms.
TNF-, which elicited both Th1 and Th2 characteristics depending on
experimental conditions, down-regulated B7.2, but did not alter B7.1
expression. None of the other cytokines, including IL-1, IL-1,
IL-2, IL-5, IL-6, and IL-12, modulated the expression of B7 isoforms
(22). B7.1 and B7.2 have different affinities for their
binding partners on T cells, CD28 and CTLA-4, and the differential
roles of B7.1 and B7.2 have been suggested for the initial, sustained T
cell activation or termination of T cell activation (20, 21). Previously, we demonstrated that histamine regulated the
IL-18-initiating cytokine cascade through down-regulation of ICAM-1
expression on monocytes (23). The changes may result in a
shift of Th1/Th2 balance toward Th2 dominance (23, 24).
Thus, many kinds of chemical mediators in inflammation may modulate
immune responses by regulation of the expression of adhesion
molecules.
PGE2, the major arachidonic acid metabolite released from APC, primes naive human T cells for enhanced production of anti-inflammatory cytokines and inhibition of proinflammatory cytokines through cyclooxygenase 2 (COX-2)3 (25, 26). The actions of PGE2 are expected to be exerted via stimulation of the four PGE2 receptor subtypes, EP1, EP2, EP3, and EP4, alone or in combination. EP1 and EP3 are coupled to a Gq protein, phosphatidylinositol production, and increased intracellular Ca2+ concentration (23). EP2 and EP4 are coupled to a Gs protein, adenylyl cyclase activation, and cAMP production (26). EP2Rs directly inhibit T cell proliferation, while EP2 and EP4Rs regulate APC functions (27). There are at least three variants of EP3, and these variants can cause increased intracellular Ca2+ concentration or the activation or inhibition of adenylate cyclase (28). While little is known about EP3R signaling, the cAMP formation induced by the activation of endogenous EP4Rs is strongly blocked by EP1R or EP3R stimulation in hamster ovary cells and human embryonic kidney 293 cells (29, 30). EP4Rs can also be distinguished pharmacologically from EP1 and EP3 receptors (26, 27). EP2Rs play an important role in uterine implantation (31, 32) and a relaxant role in bronchioles (26, 28, 32) and salt-sensitive hypertension (31, 32). A particular role for the EP4R was suggested in regulating the perinatal closure of the pulmonary ductus arteriosus (33).
In the present study, we designed experiments to examine whether IL-18 affects the expression of B7.1 and/or B7.2 on human monocytes, in addition to ICAM-1, using FACS analysis. Second, we investigated the effects of exogenous PGE2 on the IL-18-induced changes in the expression of ICAM-1, B7.1, and B7.2 and characterized the receptor subtypes involved in the action of PGE2 using selective receptor agonists. We found that PGE2 regulated the expression of ICAM-1 and B7.2 on monocytes through stimulation of specific receptor subtypes.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Recombinant human IL-18 was purchased from MBL (Nagoya, Japan). PGE2 was purchased from Sigma-Aldrich (St. Louis, MO). ONO-D1-004, ONO-AE1-259-01, ONO-AE-248, ONO-AE1-329, and 11-deoxy-PGE1 were provided by Ono Pharmaceutical (Tokyo, Japan). Dibutyryl cAMP and forskolin were purchased from WAKO (Tokyo, Japan). For flow cytometric analysis, FITC-conjugated mouse IgG1 mAb against CD54 (6.5B5) and PE-conjugated anti-CD3, anti-CD14, or anti-CD19 mAb were purchased from DAKO (Glostrup, Denmark). FITC-conjugated mouse IgG1 mAb against B7.1 (MAB104) was purchased from Immunotech (Marseilles, France). FITC-conjugated mouse IgG1 mAb against B7.2 (2331FUN-1) was purchased from BD PharMingen (San Diego, CA). FITC-conjugated MOPC 21, an IgG1 class-matched control (CMC), was purchased from Sigma-Aldrich.
Isolation and culture of PBMC
Normal human PBMC were obtained from human volunteers after they gave their oral informed consent. Samples of 20–50 ml peripheral blood were withdrawn from a forearm vein. PBMC were isolated from the buffy coat of 10 healthy volunteers by centrifugation on Ficoll-Paque (Pharmacia, Uppsala, Sweden), then washed three times in RPMI 1640 (Nissui, Tokyo, Japan) supplemented with 10% (v/v) heat-inactivated FCS, 20 µg/ml kanamycin, and 100 µg/ml streptomycin and penicillin (Sigma-Aldrich). PBMC were suspended at a final concentration of 1 x 106 cells/ml in RPMI 1640 medium supplemented with 10% (v/v) heat-inactivated FCS.
Flow cytometric analysis
PBMC (1 x 106 cells/ml) were incubated with IL-18, PGE2, EPR agonists, dibutyryl cAMP, and/or forskolin for 24 h at 37°C in a 5% CO2/air mixture under different conditions. The cells (5 x 105 cells/sample) were washed once with washing buffer (PBS supplemented with 2.5% normal horse serum, 0.1% NaN3, and 0.01 M HEPES, pH 7.3). Then the cells were incubated with 1 µg FITC-conjugated anti-ICAM-1Ab, anti-B7.1 Ab, anti-B7.2 Ab or CMC, or PE-conjugated anti-CD3 Ab, anti-CD14 Ab, or anti-CD19 Ab for 20 min at 4°C. After washing, the cells were fixed with 2% paraformaldehyde and analyzed with a FACSCalibur (BD Biosciences, San Jose, CA), and data were processed using the CellQuest program (BD Biosciences). The data are expressed as the relative fluorescence intensities against CMC. The results are the mean ± SEM of five donors.
Cytokine assay
PBMC (1 x 106 cells/ml) were
incubated with IL-18 in the presence or the absence of anti-ICAM-1,
anti-B7.1 (MAB104), and/or anti-B7.2 (2331FUN-1) Ab for 24
h at 37°C in a humidified atmosphere of 5% CO2
in air. After culture, the cell-free supernatant fractions were assayed
for IL-12, TNF-, IFN-, and IL-10 protein as described previously
(23). ELISA for IL-12 detected p70 protein.
Statistical examination
The statistical significance of differences was evaluated by ANOVA, followed by Student’s two-tailed t test. A value of p < 0.05 was considered statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The effects of IL-18 (100 ng/ml) and/or PGE2
(10-6 M) on changes in the expression of human
leukocyte Ags (ICAM-1/CD54, B7.1/CD80, and B7.2/CD86) were examined by
double-staining labeling flow cytometry using combinations of
anti-CD14, anti-CD3, and anti-CD19 Abs after 24 h of
incubation of PBMC. IL-18 (100 ng/ml) produced up-regulation of ICAM-1
and B7.2 specifically on monocytes, but not on T or B cells (Fig. 1
). In contrast, IL-18 (100 ng/ml) showed
no effect on B7.1 expression on any of these cell types (Fig. 1). PGE2 (10-6 M)
inhibited ICAM-1 and B7.2 expression induced by IL-18 (100 ng/ml; Fig. 1). The same concentration of PGE2 alone did not
influence ICAM-1 or B7.2 expression on monocytes.
|
The time courses of changes in the expression of ICAM-1, B7.1, and
B7.2 on monocytes induced by IL-18 were examined 0, 2, 6, 18, and
24 h after the start of incubation. IL-18 (100 ng/ml) up-regulated
ICAM-1 and B7.2 expression on monocytes in a time-dependent manner
(Fig. 2). The effect of IL-18 on ICAM-1
expression was significant at 12 and 24 h, whereas that on B7.2
was significant at 24 h. IL-18 did not induce the expression of
B7.1 at any time point examined.
|
We examined the effects of different concentrations of IL-18 on
the expression of ICAM-1, B7.1, and B7.2 by flow cytometry after
24 h of incubation of PBMC (Fig. 3).
IL-18 (0.1–100 ng/ml) up-regulated the expression of ICAM-1 and B7.2,
but not that of B7.1, on monocytes in a concentration-dependent manner
(Fig. 3). The threshold concentrations for the significant effects of
IL-18 on ICAM-1 and B7.2 expression were 10 and 100 ng/ml,
respectively, compared with the buffer control.
|
The effects of PGE2 on the changes in IL-18
(100 ng/ml)-induced expression of ICAM-1, B7.1, and B7.2 were
determined 24 h after the start of culture (Fig. 4). PGE2
(10-9–10-5 M) had no
effect on ICAM-1, B7.1, or B7.2 expression on monocytes without IL-18
treatment. However, PGE2 down-regulated IL-18
(100 ng/ml)-induced ICAM-1 and B7.2 expression on monocytes in a
concentration-dependent manner (Fig. 4). The IC50
values for the inhibitory effect of PGE2 on the
expression of ICAM-1 and B7.2 induced by IL-18 were estimated to be the
same, 50 nM.
|
To determine the PGE2 receptor
subtypes involved in the effects of PGE2 on
ICAM-1 and B7.2 expression, we examined the effects of EPR agonists
(10-9–10-5 M) on ICAM-1,
B7.1, and B7.2 expression on monocytes induced by IL-18 (100 ng/ml)
after 24-h incubation of PBMC. ONO-D1-004 (EP1R agonist) (34, 35), and ONO-AE-248 (EP3R agonist) (33, 34, 35), in the
concentration range from 10-9 to
10-5 M, had no effect on ICAM-1, B7.1, or B7.2
expression induced by IL-18 (Fig. 5A). On the other hand,
ONO-AE1-259-01 (EP2R agonist) (34, 35, 36) inhibited ICAM-1
and B7.2 expression on IL-18-treated monocytes in a
concentration-dependent manner (Fig. 5). ONO-AE1-329 (EP4R agonist)
(34, 35, 36) also inhibited ICAM-1 and B7.2 expression on
monocytes with IL-18; however, the potency of the inhibitory effect of
ONO-AE1-329 on ICAM-1 expression was lower than that of ONO-AE1-259-01.
IC50 values for the inhibitory effect of
ONO-AE1-259-01 on the expression of ICAM-1 was estimated to be 100 nM
(Fig. 5). Moreover, we confirmed that
11-deoxy-PGE1 (EP2R/EP4R agonist) (36, 37), inhibited IL-18-induced ICAM-1 and B7.2 expression in a
concentration-dependent manner (Fig. 6).
Thus, EP2 and EP4Rs are involved in the down-regulation of
IL-18-elicited ICAM-1 and B7.2 expression by
PGE2. The IC50 values for
the inhibitory effect of 11-deoxy-PGE1 on the
expression of ICAM-1 and B7.2 were estimated to be the same, 50 nM. At
10-6 and 10-5 M,
11-deoxy-PGE1 blocked the expression of ICAM-1
and B7.2 completely.
|
|
To investigate the mechanism by which PGE2
inhibited ICAM-1 and B7.2 expression elicited by IL-18, the effects of
dibutyryl cAMP, a membrane-permeable cAMP analog, and forskolin, an
adenylate cyclase activator, on the IL-18-induced expression of ICAM-1
and B7.2 on monocytes were examined (Fig. 7). Dibutyryl cAMP and forskolin
(10-7–10-4 M)
down-regulated IL-18-induced ICAM-1 and B7.2 expression in a
concentration-dependent manner. The IC50 values
of dibutyryl cAMP and forskolin in ICAM-1 and B7-2 expression were the
same, 5 µM. These results indicated that an increase in intracellular
cAMP level can mimic the effects of EP2/4R stimulation.
|
We investigated the effects of anti-ICAM-1, anti-B7.1, or
anti-B7.2 Ab on IL-18-induced cytokine production to evaluate the
possible involvement of ICAM-1, B7.1, or B7.2 in the response (Fig. 8). Fig. 8 shows that anti-ICAM-1 Ab
or anti-B7.2 Ab down-regulated IL-18-induced IL-12, TNF-, and
IFN- production, whereas both Abs up-regulated IL-10 production in a
concentration-dependent manner. Anti-B7.1 Ab had no effect on these
cytokine responses. The maximal effects obtained with anti-ICAM-1
Ab or anti- B7.2 Ab were 60 and 30%, respectively, regardless of
the kinds of cytokines produced by IL-18. The combination of
anti-ICAM-1 and anti- B7.2 Ab produced 
80% inhibition of
the cytokine responses induced by IL-18. The class-matched nonrelevant
Ab at a concentration of 100 µg/ml had no effect on IL-18-induced
cytokine responses.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, and IFN-
(18). Therefore, the IL-18-initiated cytokine cascade was
suggested to be dependent on the up-regulation of ICAM-1 on monocytes
and subsequent interaction of ICAM-1 on monocytes and LFA-1 on T/NK
cells (18). In the present study we also demonstrated that
IL-18 up-regulated B7.2, but not B7.1, on monocytes in addition to
ICAM-1 (
Figs. 1–3
). The fact that anti-B7.2 Ab, but not
anti-B7.1 Ab, inhibited the production of IL-12, TNF-, and
IFN- (Fig. 8) suggested that the interaction of B7.2 with CD28 is
also involved in cytokine cascade induced by IL-18 in addition to
ICAM-1/LFA-1 interaction. The extent of the inhibition of IL-18-induced
cytokine response by anti-B7.2 was smaller than that by
anti-ICAM-1. Therefore, it is likely that the ICAM-1/LFA-1
interaction is relatively important for IL-18 action in human PBMC. The
costimulatory molecules on APC, including B7.2, have been suggested to
be involved in the diversity of T cell responses (21).
B7.2/CD28 interaction was suggested to be required for initial T cell
costimulation during Ag presentation because of the constitutive
expression and relatively rapid induction of B7.2 on APC, whereas
B7.1/CD28 interaction may be involved in the sustained T cell
activation because of the slow induction of B7.1 expression with low
expression levels in the resting T cells (20, 21). In this
context, IL-18 may be able to facilitate the initial T cell response
through the up-regulation of B7.2 expression on monocytes. Although the
functional profile of IL-18 appears to be similar to that of IL-12, the
up-regulating effect of IL-18 on B7.2 was distinct from that of IL-12
(22).
In the present study, we clearly demonstrated inhibitory effects of
PGE2 on the expression of ICAM-1 and B7.2 on
monocytes elicited by IL-18 (Figs. 1, 3, and 4). These modulatory
effects were similar to those of histamine (23), another
important chemical mediator in inflammatory and immune responses.
To investigate the receptor subtypes involved in the action of
PGE2, we used selective agonists for respective
receptors (34). ONO-AE1-259 and ONO-AE-1-329 were
demonstrated to be highly selective for mouse EP2 and EP4
receptors, respectively, using a receptor binding assay in Chinese
hamster ovary cells transfected with each EP cDNA
(34). Suzuwa et al. (34) reported that the
selective EP1R–EP4R agonists used in the present study were highly
selective for their respective receptors. For example, the EP2R agonist
ONO-AE1-259 had at least 700-fold higher affinity for EP2Rs compared
with other receptor agonists (34). In the present study
the IC50 values for the inhibitory effects of
ONO-AE1-259 and ONO-AE-1-329 on the expression of ICAM-1 on monocytes
induced by IL-18 were similar (50 and 100 nM, respectively; Fig. 5).
Therefore, these findings indicated that EP2 and EP4 receptor agonists
stimulated respective receptors and both EP2 and EP4 receptors were
involved in the PGE2-initiated down-regulation of
ICAM-1 and B7.2 expression elicited by IL-18. It is unlikely that
either of the receptor agonists stimulated the other receptors at the
concentration range used, judging from the selectivity of each agonist.
The observation that 11-deoxy-PGE1, a mixed
EP2R/EP4R agonist, mimicked the inhibition of IL-18-induced ICAM-1 and
B7.2 expression by PGE2 (Fig. 6) was consistent
with the above conclusion.
EP2 and EP4 receptors were repeatedly demonstrated to be
coupled with adenylate cyclase (26). As shown in Fig. 7, the findings that forskolin and dibutyryl cAMP mimicked the effects of
PGE2 on ICAM-1 and B7.2 expression were
consistent with the intracellular signaling pathway stimulated by EP2
and EP4 receptors. Monocytes/macrophages are known to express COX-1 and
COX-2 (40, 41). When stimulated with LPS, zymosan, or
polymerized bovine albumin (40, 41), the expression of
COX-2 was specifically up-regulated, leading to enhanced production of
PGE2. LPS stimulates monocytes/macrophages
through CD14R/Toll-like receptor 4 and activates multiple signal
transduction pathways, including IL-1R-associated kinase-mediated
activation of NF-
B and c-Jun N-terminal kinase. Some of the pathways
appear to be shared by IL-18R signaling (42), because
Toll-like receptor 4 and IL-18R have homologous IL-1R-like
intracellular domains. However, IL-18 did not induce
PGE2 production in human PBMC (43),
but, rather, inhibited PGE2 production in an
IFN--dependent manner. Therefore, it is likely that the endogenous
production of PGE2 in PBMC did not occur under
the present conditions. Previously, we demonstrated that IFN-
production induced by IL-18 in human PBMC was totally dependent on the
interaction between ICAM-1 on monocytes and LFA-1 on NK/T cells
(18). Thus, IFN--dependent inhibition of
PGE2 production by IL-18 may facilitate IFN-
production by IL-18.
The recent development of mouse lines with targeted mutations of genes encoding enzymes and receptors in the prostanoid pathway has enabled evaluation of the functional roles of prostanoids in complex inflammatory and immune responses (27, 44, 45). Using mouse lines with disrupted genes encoding each of the four EPRs, Nataraj et al. (27) demonstrated that EP2Rs and EP4Rs play major roles in the inhibitory effects of PGE2 on cell proliferation as well as cytokine release in the MLR with EP2 dominance, whereas EP1 and EP3 did not alter the inhibitory response to PGE2. These profiles of the involvement of EPR subtypes in cellular immune responses were quite similar to the regulatory effects of EPR agonists on ICAM-1 and B7.2 expression in the present study. Therefore, it is possible that some of the inhibitory effects of PGE2 in MLR in wild-type responder cells may be due to inhibition of the expression of ICAM-1 and B7.2, leading to reduction of costimulatory signals in responding T cells. Further studies are necessary to clarify this point.
In patients with injury, infection, or cancer, elevated PGE2 levels contribute to the inhibition of cellular immunity through cAMP production (46, 47). On the other hand, in transplantation, PGE2-induced elevation of cAMP exerts a beneficial effect on allograft survival by modulating T cell function (48). Enhanced PGE2 production reduces Th1 cytokine levels, independently of those of Th2 cytokines, in the local graft environment after donor-specific blood transfusion, which induces donor-specific intragraft suppressor factors, accompanied by reduced local and systemic immune activation (49). Therefore, stable PGE2 analogs may be useful for the treatment of Th1-mediated inflammatory diseases. PGE2-induced down-regulation of IL-18-induced ICAM-1 and B7.2 expression may result in the control of inflammatory and immune responses. In conclusion, the results of the present study suggested that PGE2 down-regulated ICAM-1 and B7.2 expression on IL-18-stimulated monocytes through a cAMP-dependent mechanism via stimulation of EP2R/EP4Rs, leading to modulation of immune responses by changing cell to cell interactions through ICAM-1/LFA-1 and B7.2/CD28.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Masahiro Nishibori, Department of Pharmacology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. E-mail address: mbori{at}md.okayama-u.ac.jp
3 Abbreviations used in this paper: COX, cyclooxygenase; CMC, class-matched control.
Received for publication December 3, 2001. Accepted for publication February 26, 2002.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
production by T cells. Nature 378:88.[Medline]
inducing factor mediated by interleukin-1 converting enzyme. Science 275:206.-inducing factor and regulates LPS-induced IFN- production. Nature 386:619.[Medline]
-inducing factor (IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12. J. Immunol. 158:1541.[Abstract]
-inducing factor in enhanced production of IFN-. J. Immunol. 159:2125. promoter in primary CD4+ T lymphocytes. J. Immunol. 160:3642. in response to IL-18. J. Immunol. 160:3759. production in PBMC. Cell. Immunol. 210:106.[Medline]
-inducing factor, a novel cytokine, up-regulates ICAM-1 (CD54) expression in KG-1 cells. J. Leukocyte Biol. 64:519.[Abstract]
production by IL-12 and IL-18. Curr. Opin. Immunol. 10:259.[Medline]
-induced prostaglandin production via inhibition of IFN-. Proc. Natl. Acad. Sci. USA 97:2174.This article has been cited by other articles:
|
|
 |
|
  M. A. Alvarez-Soria, G. Herrero-Beaumont, O. Sanchez-Pernaute, M. Bellido, and R. Largo Diacerein has a weak effect on the catabolic pathway of human osteoarthritis synovial fibroblast--comparison to its effects on osteoarthritic chondrocytes Rheumatology, May 1, 2008; 47(5): 627 - 633. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. K. Takahashi, H. Iwagaki, R. Hamano, T. Yoshino, N. Tanaka, and M. Nishibori Effect of nicotine on IL-18-initiated immune response in human monocytes J. Leukoc. Biol., December 1, 2006; 80(6): 1388 - 1394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. K. Takahashi, H. Iwagaki, D. Xue, G. Katsuno, S. Sugita, K. Mizuno, S. Mori, S. Saito, T. Yoshino, N. Tanaka, et al. Effect of Ciprofloxacin-Induced Prostaglandin E2 on Interleukin-18-Treated Monocytes Antimicrob. Agents Chemother., August 1, 2005; 49(8): 3228 - 3233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. K. Takahashi, S. Mori, H. Iwagaki, T. Yoshino, N. Tanaka, G. Weitz-Schmidt, and M. Nishibori Differential effect of LFA703, pravastatin, and fluvastatin on production of IL-18 and expression of ICAM-1 and CD40 in human monocytes J. Leukoc. Biol., March 1, 2005; 77(3): 400 - 407. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Gerlo, P. Verdood, B. Gellersen, E. L. Hooghe-Peters, and R. Kooijman Mechanism of Prostaglandin (PG)E2-Induced Prolactin Expression in Human T Cells: Cooperation of Two PGE2 Receptor Subtypes, E-Prostanoid (EP) 3 and EP4, Via Calcium- and Cyclic Adenosine 5'-Monophosphate-Mediated Signaling Pathways J. Immunol., November 15, 2004; 173(10): 5952 - 5962. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R Largo, I Diez-Ortego, O Sanchez-Pernaute, M J Lopez-Armada, M A Alvarez-Soria, J Egido, and G Herrero-Beaumont EP2/EP4 signalling inhibits monocyte chemoattractant protein-1 production induced by interleukin 1{beta} in synovial fibroblasts Ann Rheum Dis, October 1, 2004; 63(10): 1197 - 1204. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Aronoff, C. Canetti, and M. Peters-Golden Prostaglandin E2 Inhibits Alveolar Macrophage Phagocytosis through an E-Prostanoid 2 Receptor-Mediated Increase in Intracellular Cyclic AMP J. Immunol., July 1, 2004; 173(1): 559 - 565. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kubo, H. K. Takahashi, M. Takei, H. Iwagaki, T. Yoshino, N. Tanaka, S. Mori, and M. Nishibori E-Prostanoid (EP)2/EP4 Receptor-Dependent Maturation of Human Monocyte-Derived Dendritic Cells and Induction of Helper T2 Polarization J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 1213 - 1220. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. P. J. Hofer, E. Bitterle, I. Beck-Speier, K. L. Maier, M. Frankenberger, J. Heyder, and L. Ziegler-Heitbrock Diesel exhaust particles increase LPS-stimulated COX-2 expression and PGE2 production in human monocytes J. Leukoc. Biol., May 1, 2004; 75(5): 856 - 864. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. K. Takahashi, H. Iwagaki, R. Tamura, D. Xue, M. Sano, S. Mori, T. Yoshino, N. Tanaka, and M. Nishibori Unique Regulation Profile of Prostaglandin E1 on Adhesion Molecule Expression and Cytokine Production in Human Peripheral Blood Mononuclear Cells J. Pharmacol. Exp. Ther., December 1, 2003; 307(3): 1188 - 1195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Carey, D. R. Germolec, J. A. Bradbury, R. A. Gooch, M. P. Moorman, G. P. Flake, R. Langenbach, and D. C. Zeldin Accentuated T Helper Type 2 Airway Response after Allergen Challenge in Cyclooxygenase-1-/- but Not Cyclooxygenase-2-/- Mice Am. J. Respir. Crit. Care Med., June 1, 2003; 167(11): 1509 - 1515. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Morichika, H. K. Takahashi, H. Iwagaki, T. Yoshino, R. Tamura, M. Yokoyama, S. Mori, T. Akagi, M. Nishibori, and N. Tanaka Histamine Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-{alpha} Production in an Intercellular Adhesion Molecule-1- and B7.1-Dependent Manner J. Pharmacol. Exp. Ther., February 1, 2003; 304(2): 624 - 633. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
|
, Fluorescence intensity obtained with CMC after
incubation in the presence of IL-18, respectively. The results are the
mean ± SEM of five donors. *, p < 0.05; **,
p < 0.01 (compared with 0 h value). Where error
bars are not shown, they were smaller than the symbol.
, Results obtained
with anti-ICAM-1 Ab, anti-B7.1 Ab, or anti-B7.2 Ab after
incubation in the presence or the absence of IL-18, respectively. 
, Fluorescence intensity obtained with CMC after incubation in
the presence or the absence of IL-18, respectively. The results are the
mean ± SEM of five donors. *, p < 0.05; **,
p < 0.01 (compared with the value in the absence of
PGE2). Where error bars are not shown, they were smaller
than the symbol.
