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*
Clinical Immunology Section and
Medical Virology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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in a dose-responsive manner. Moreover, PBMCs stimulated with
immobilized anti-CD3 in the presence of PGE2 or DXM for
3 days, washed extensively, and restimulated in the presence of IL-12
still did not produce IFN-. This lack of IL-12 responsiveness from
cells cultured in either PGE2 or DXM was correlated with
diminished surface expression of IL-12Rß1, IL-12Rß2 mRNA
expression, and IL-12 binding. Finally, the PGE2- and
DXM-mediated inhibition of IL-12R expression was not affected
significantly by addition of neutralizing Abs against either IL-4,
IL-10, or TGF-ß. By contrast, addition of dibutyryl cAMP,
8-bromoadenosine 3:5 cAMP (8-Br-cAMP), or cholera toxin substantially
reduced IL-12R expression, suggesting that PGE2 may be
mediating its effects through enhancement of
cAMP. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production and in Th1 differentiation (6).
Due to the importance of IL-12 responsiveness to biologic function,
there has been interest in understanding the factors involved in
regulating IL-12R. Human in vitro studies have shown that IL-12Rß1 is
expressed at low levels on freshly isolated PBMCs (7). Activation of
PBMCs with mitogens or anti-CD3 mAb leads to up-regulation of
IL-12Rß1 expression and IL-12 binding (7). The maximum expression of
IL-12Rß1 and IL-12 binding in PBMCs or mRNAs for IL-12Rß1 and
IL-12Rß2 in CD4 T cells required stimulation with anti-CD3 plus
costimulation with either anti-CD28 mAb (7) or B7-2-transfected
Chinese hamster ovary cells (8). Additional positive regulators of
IL-12Rß1 expression and IL-12 binding include IL-2, IL-7, and
IL-15 (7). By contrast, negative regulators of IL-12Rß1 expression
and IL-12 binding include TGF-ß, IL-4, and IL-10 (7, 9). Of interest,
regulation of IL-12Rß2 mRNA transcripts in mouse and humans appears
to be different. Thus, IFN- in mice (10) and IFN-
in humans (11)
appear to regulate IL-12Rß2 mRNA expression using in vitro priming
cultures.
In addition to cytokines, certain biochemical mediators and hormones have been shown to have potent immunoregulatory functions. With regard to Th cell differentiation, PGE2, an arachidonic acid metabolite released from various cells including APCs, has been shown to suppress T cell proliferation (12, 13, 14) and to inhibit the differentiation of Th1 cells (15, 16, 17, 18, 19, 20). These latter effects have been supported by the observation that PGE2 can suppress IL-12 production by monocytes and dendritic cells (21); however, in some studies, it should be noted that PGE2 can also enhance IL-12 production from human dendritic cells (22). Similarly, corticosteroids, commonly used immunosuppressive agents, have also been shown to exert potent inhibitory function on developing Th1 responses through inhibition of IL-12 (23, 24).
In this study, PGE2 and dexamethasone (DXM)2 are shown to inhibit responsiveness of activated human PBMCs and T cells to IL-12 through the suppression of IL-12Rß1 expression and IL-12Rß2 mRNA transcription. These inhibitory effects of PGE2 and DXM on IL-12R expression were not affected substantially by addition of neutralizing Abs to IL-4, IL-10, or TGF-ß; however, cAMP analogues were found to inhibit IL-12Rß1 expression. Taken together, these data are consistent with the striking antiinflammatory properties of DXM, and also suggest that PGE2 may, in fact, suppress inflammation through increasing cAMP.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Complete cell culture medium consists of RPMI 1640 supplemented with 10% heat-inactivated human AB sera (Sigma, St. Louis, MO), penicillin (100 U/ml), streptomycin (100 U/ml), and L-glutamine (2 mM). All were purchased from Biofluids (Rockville, MD). Lymphocyte separation medium was purchased from Organon Teknika (Durham, NC). PGE2 and DXM were purchased from Sigma. Anti-CD3 (OKT3) mAb was purified from ascites. Neutralizing mAbs to human IL-4, TGF-ß, and IL-10 were purchased from PharMingen (Torrance, CA). Purified human IL-12, biotinylated anti-human IL-12 mAb 4D6 (B-4D6), biotinylated anti-human IL-12Rß1 mAb 2.4E6 (B-2.4E6), and IL-12Rß2 cDNA probe for Northern blot analysis were kindly provided by Drs. M. Gately and U. Gubler, respectively (Department of Inflammation/Autoimmune Diseases, Hoffmann-La Roche, Nutley, NJ). cAMP analogues 8-bromoadenosine 3:5 cyclic monophosphate (8-Br-cAMP), N6, and 2-o-dibutyryladenosine 3:5 cyclic monophosphate (dibutyryl cAMP) were purchased from Sigma and used at concentrations of 1 mM. Cholera toxin was purchased from Sigma and used at 100 ng/ml.
Cell isolation and culture conditions
PBMCs were isolated from buffy coats by density-gradient centrifugation over lymphocyte separation medium. T cells were isolated by rosetting with neuraminidase-treated SRBCs. Rosette-forming cells were lysed with ACK lysing buffer (Biofluids), washed in HBSS, and resuspended in complete cell culture medium. For activation, PBMCs at 1 x 106 cells/ml in cell culture medium were stimulated with anti-CD3 mAb at concentrations of 5 µg/ml. In addition, purified T cells (1 x 106 cells/ml) were stimulated with immobilized anti-CD3 mAb in 24-well tissue culture plates (Costar, Cambridge, MA) that had been coated overnight at 4°C with 5 µg/ml anti-CD3 mAb in coating buffer (0.05 M sodium carbonate buffer, pH 9.6) and washed three times with PBS before use. After incubation for 3 days, cells were harvested, washed, and assayed for the expression of IL-12Rß1 and IL-12 binding by flow cytometry.
Flow-cytofluorometric analysis
The methods used for the detection of IL-12Rß1 and IL-12 binding cells by flow cytometry have been described previously (5, 7). Briefly, to evaluate expression of IL-12Rß1, cells were incubated with biotinylated anti-IL-12Rß1 mAb 2.4E6 (B-2.4E6), followed by streptavidin conjugated to phycoerythrin (S-PE; PharMingen). For detection of IL-12 binding, cells were incubated with unlabeled IL-12, followed by biotinylated, nonneutralizing anti-IL-12 mAb 4D6 (B-4D6), and finally with S-PE. Stained cell populations were analyzed on a FACScan (Becton Dickinson, Mountain View, CA). The mean fluorescence intensity (MFI) difference was calculated by subtracting the MFI for cells stained with isotype control Ab or with B-4D6 alone from the MFI for cells stained with B-4D6 or with IL-12 plus B-4D6, respectively.
Proliferation and IFN- production assays
Cell cultures were performed as previously described (7). PBMCs
were incubated at a final density of 1 x 106/ml in
complete culture medium with 5 µg/ml anti-CD3 mAb in the presence
or absence of concentrations of PGE2 or DXM. All cultures
were conducted in six-well plates in a total volume of 4 ml/well. After
incubation for 3 days at 37°C, the lymphoblasts were collected and
extensively washed. For measurement of cytokine-induced proliferation,
anti-CD3-activated lymphoblasts were incubated in 96-well plates
(Costar) at a final cell density of 2 x 105 cells/0.2
ml with either IL-12 or IL-2. After incubation for 2 days at 37°C,
the cultures were pulsed with [3H]thymidine (New England
Nuclear, Boston, MA) for 6 to 8 h. [3H]Thymidine
incorporation into cellular DNA was measured in triplicate samples. For
production of IFN-, anti-CD3-activated lymphoblasts were
incubated at a final density of 2 x 105 cells/0.2 ml
in complete culture medium in the presence or absence of varying
concentrations of IL-12. All cultures were conducted in triplicate in
96-well plates. After incubation for 48 h at 37°C, the
supernatant fluids were harvested and assayed in triplicate for
IFN-.
Measurement of IFN- production
The levels of IFN- in the culture fluids were determined by a
two-step specific ELISA, according to the manufacturer’s suggestions
(Endogen, Woburn, MA; lower limit of detection at 50–100 pg/ml).
Results for all cytokines represent the mean of triplicate wells. The
SEM was <10% for all experiments.
RNA preparation and Northern blot analysis
PBMCs were cultured with medium alone or with anti-CD3 mAb in the presence or absence of PGE2 and DXM. After incubation for 48 h, cells were harvested and total RNA was isolated using the RNA STAT-60 reagent (TEL-TEST, Friendswood, TX) following the instructions of the manufacturer. For Northern blot analysis, 25 µg of total RNA per sample was denatured and electrophoresed on formaldehyde-denaturing gel and transferred to a nylon membrane (Schleicher & Schuell, Keene, NH). An IL-12Rß2 cDNA fragment encompassing the coding region was labeled with [32P]dCTP using the Multiprime DNA labeling system (Amersham, Arlington Heights, IL). Hybridization was conducted overnight at 42°C in a buffer containing 50% formamide, 0.5% SDS, 10% dextran sulfate, 6x SSC, 100 µg/ml denatured sheared DNA, and 5 x 106 cpm/ml probe. Northern blot was washed three times at room temperature in a buffer containing 2x SSC/0.1% SDS, then washed twice at 65°C for 20 min in 0.2x SSC/0.1% SDS, and finally washed twice at 70°C for 20 min in 0.1x SSC/0.5% SDS. The membrane was subjected to autoradiography and PhosphorImager quantitation. The probe was then stripped by washing with 0.1x SSC/0.5% SDS for 20 min twice at 90 to 100°C. The membrane was rehybridized as above with a probe of human 28S rRNA for the assessment of equal loading.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production from PBMCs
stimulated with anti-CD3 plus IL-12 in primary or secondary culture
In previous studies, both PGE2 (16, 17, 18) and DXM (23)
were shown to inhibit production of IFN- from human PBMCs stimulated
with mitogens. One mechanism by which PGE2 and DXM mediate
this effect is through their ability to inhibit IL-12 production (21, 23). An additional mechanism could be through their effects on
inhibiting IL-12 responsiveness. To this end, PBMCs were stimulated
with plate-bound anti-CD3 and IL-12 in the presence of varying
concentrations of PGE2 or DXM, and IFN- production was
assessed. As shown in Figure 1
,
A and B, addition of PGE2 or DXM,
respectively, resulted in a striking decrease in production of IFN-
in a dose-dependent manner. To further determine whether the effects of
PGE2 and DXM impaired the subsequent ability of the cells
to respond to IL-12, PBMCs were first stimulated for 3 days with
anti-CD3 in the presence of PGE2 or DXM, washed
extensively, and restimulated with varying concentrations of IL-12. As
shown in Figure 2, the presence of
PGE2 or DXM in primary cultures abrogated the ability of
IL-12 to induce production of IFN- (Fig. 2A) or enhance
proliferation (Fig. 2B) in secondary cultures. As a control,
cells cultured in PGE2 or DXM maintained IL-2
responsiveness in secondary cultures (Fig. 2C). It should be
noted, however, that PGE2 did inhibit IL-2R chain
expression (data not shown). Implications for these data are discussed
below.
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Since the data above showed that PGE2 and DXM impaired
IL-12 responsiveness, the effect they had on IL-12R expression was
assessed. As shown in Figure 3, PBMCs
stimulated with plate-bound anti-CD3 and varying concentrations of
PGE2 (Fig. 3A) or DXM (Fig. 3B) had a
dose-dependent decrease in IL-12Rß1 expression. Moreover, this
correlated with a decrease in IL-12 binding (Fig. 3, C and
D).
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As the previous experiments were done using PBMCs, it was of
interest to see whether the effects of PGE2 and DXM on
IL-12 responsiveness were on T cells. As shown in Figure 4, both PGE2 and DXM
inhibited IL-12Rß1 expression and IL-12 binding on purified T cells.
In addition, in experiments not shown, PBMCs stimulated with
anti-CD3 in the presence of PGE2 and DXM had a
reduction in IL-12Rß1 expression on cells double stained with CD3 or
CD16/CD56 and IL-12Rß1. Taken together, these data show that
PGE2 and DXM inhibit IL-12Rß1 expression on T cells and
on NK cells.
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IL-12R is composed of at least two chains (3). The previous
experiments focused on expression of the IL-12Rß1 protein. To
determine whether PGE2 or DXM also inhibited the
IL-12Rß2 subunit, PBMCs were stimulated with or without plate-bound
anti-CD3 in the presence or absence of DXM or PGE2 for
48 h, and mRNA expression for IL-12Rß2 was assessed by Northern
blot analysis. As shown in Figure 5,
there was no IL-12Rß2 mRNA expression from cells cultured in medium
alone, while there was an approximately 4-kb band noted from cells
stimulated with anti-CD3 alone, consistent with previous data
showing that activation is required to induce this receptor subunit (3, 10, 11). Addition of PGE2 or DXM strikingly diminished the
mRNA expression for IL-12Rß2 (Fig. 5A). Moreover,
additional quantitative analysis using a PhosphorImager shows that the
ratio of IL-12Rß2:28S rRNA was diminished three- to fourfold in cells
stimulated in the presence of PGE2 and DXM (Fig. 5B). Thus, taken together with the previous figures, these
data confirm that PGE2 or DXM down-regulates both chains of
the IL-12R.
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Finally, it was of interest to determine the mechanism by which
PGE2 and DXM inhibited IL-12R expression. In this regard,
previous work in both mouse and human studies has shown that cytokines
such as IL-10, IL-4, and TGF-ß all inhibit IL-12Rß1 expression (7).
Moreover, PGE2 has been shown to increase production of
IL-10 (18, 21, 25). To examine whether PGE2 and DXM were
acting directly or indirectly via induction of inhibitory cytokines,
PBMCs were stimulated in the presence of PGE2 or DXM with
or without anti-IL-4, anti-IL-10, or anti-TGF-ß. As shown
in Figure 6, there appeared to be a
modest effect on reversing the inhibition of IL-12Rß1 induced by
PGE2 when all three Abs were added; however, the effects of
these cytokines on DXM inhibition were more modest.
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As cytokines did not appear to be the mechanism by which
PGE2 down-regulates IL-12Rß1 expression, it was possible
that enhancement in cAMP by PGE2 was mediating the
inhibition (26). As cAMP has been shown to affect Th1-type cytokine
production (27, 28), PBMCs or purified T cells were stimulated with
anti-CD3 in the presence of dibutyryl cAMP, 8-Br-cAMP, or cholera
toxin (an inducer of cAMP). As shown in Table I, addition of PGE2 resulted
in a 50% reduction in IL-12Rß1 expression in both PBMCs and T cells.
Moreover, dibutyryl cAMP, 8-Br-cAMP, and cholera toxin all resulted in
a striking four- to fivefold reduction in IL-12Rß1 expression. These
results suggest that cAMP has a profound effect on regulating
IL-12Rß1 expression and that PGE2 may be mediating its
effects through this pathway.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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.
The potential importance of these findings and the mechanism by which
these mediators exerted their effects are discussed below.
PGE2 inhibits the induction of type 1 cytokine
responses (IFN- and IL-12) and IL-12 responsiveness
PGE2, an arachidonic acid metabolite produced in a
variety of inflammatory and infectious diseases, may have a role in
affecting the immune response and biologic outcome in those diseases.
With regard to the effects of PGE2 on cytokine production,
there are several reports showing that PGE2 inhibits type 1
cytokine responses and enhances Th2 responses (15, 16, 17, 18, 19, 20). This effect
appears to be indirect through inhibition of IL-12 (21) and/or through
direct inhibition of IL-2/IFN- (18). In this study, we show that in
primary short-term stimulation, PGE2 inhibits the ability
of IL-12 to augment production of IFN- on PBMCs through inhibition
of IL-12R expression. In addition, cells cultured for a brief period in
the presence of PGE2 were still unresponsive to subsequent
stimulation with IL-12, suggesting that these effects are sustained at
least in a short-term secondary stimulation. It should be noted that in
a recent report (18), the presence of PGE2 in priming
cultures led to an increase in IL-4 production. In this study, we were
not able to detect IL-4 following stimulation in the presence of
PGE2 (data not shown). It is likely that differences in the
experimental conditions (e.g., type of cells used, duration and type of
stimulation) are important in regulating IL-4 production. The mechanism
by which PGE2 could be inhibiting IL-12R could be due to
several factors. First, if PGE2 caused enhanced production
of IL-4 and diminished production of IL-12 (cytokines that negatively
and positively regulate IL-12Rß1 expression, respectively), then an
indirect effect might be operative. Evidence against this was the fact
that, in these short-term culture conditions, IL-4 was not detected
(data not shown). Moreover, the fact that anti-IL-4,
anti-IL-10, and anti-TGF-ß alone did not substantially
reverse the inhibition seen with PGE2 mitigates this as a
mechanism. Second, the data showing that other inducers of cAMP such as
dibutyryl cAMP, 8-Br-cAMP, and cholera toxin (Table I
) inhibited
IL-12Rß1 expression and IL-12 binding make this the more likely
mechanism, since this is how PGE2 mediates its effects.
Whether PGE2, through cAMP, directly inhibits IL-12R
expression or indirectly mediates this effect through another mechanism
(i.e., cytokines) remains an open question. In this regard, the ability
of PGE2 to inhibit IL-2 production (18) may diminish IL-12
responsiveness, since IL-2 enhances IL-12Rß1 expression (7).
Moreover, the fact that addition of exogenous IL-2 to cells stimulated
in the presence of PGE2 restored IL-12Rß1 expression
supports this as an important mechanism (data not shown).
The role of DXM in regulating Th1/Th2 responses and IL-12 responsiveness
Due to the importance of IFN- and IL-4/IL-5 in inflammatory and
allergic diseases, respectively, the ability of corticosteroids to
affect Th cell differentiation has been of great interest. Studies
examining the effect of corticosteroid Th1- and Th2-type cells have
yielded inconsistent results due to several variables. These include
the dose of steroids used in the cultures, whether T cells are
stimulated in the presence or absence of APCs, and the stage of
differentiation at which the T cells are tested. Thus, an early report
using mouse cells stimulated in vitro showed that low-dose
corticosteroids led to increased production of IL-4 (29), while human
PBMCs stimulated with mitogens in vitro had decreased production of
IL-4 (30). In this latter report, however, IFN- was not assessed, so
specificity for IL-4 cannot be assured. In subsequent studies, the
presence of corticosteroids inhibited transcription of both IL-4 and
IFN- (31, 32); however, in one of these studies, low doses of
corticosteroids appeared to increase IL-4 (31). In a rat model of in
vitro priming, mRNA levels for IL-4, IL-10, and IL-13 were increased,
but IFN- decreased, by culturing cells in DXM (33). Finally, using
an APC-independent in vitro priming model, the presence of low-dose
corticosteroids decreased production of IL-4, IL-5, and IFN-, but
increased IL-10 using naive CD4+/CD45RO- cells
(34). Of interest, the presence of corticosteroids in the restimulation
cultures enhanced IL-4, but diminished IL-5 and IFN- (34).
More recently, the role of DXM in affecting Th cell differentiation via
its effects on IL-12 has been elucidated in two reports using mouse
(24) and human (23) in vitro culture systems. These studies show that
DXM inhibits IL-12 production from macrophages, leading to a reduction
of IFN- and increase in production of IL-4. Furthermore, in both of
these studies, addition of exogenous IL-12 was able to restore the
defect caused by DXM, suggesting that IL-12 responsiveness was
maintained. In the studies reported in this work, human PBMCs cultured
in the presence of DXM and IL-12 had a marked reduction in IFN-
production. Moreover, cells cultured with DXM alone during primary
stimulation were unresponsive to subsequent stimulation with exogenous
IL-12. Differences among these studies may be due to different in vitro
culture conditions. In our studies, PBMCs or total T cells were
stimulated with anti-CD3, and receptor expression and cytokine
production were assessed within 3 to 5 days following stimulation. By
contrast, the other studies used CD4+ T cells stimulated
with adherent cells plus PHA and PMA for a longer time (12 days) or in
multiple rounds of stimulation. Despite these differences, the
functional result is that DXM inhibits the induction of IFN-.
Finally, with regard to mechanism, addition of anti-IL-4, IL-10,
and TGF-ß did not significantly affect the inhibition of IL-12Rß1
expression or IL-12 binding by DXM.
Clinical implications of DXM affecting IL-12 responsiveness
In conclusion, since corticosteroids are among the most potent
drugs for treatment of inflammatory and allergic diseases,
understanding the mechanism by which they regulate immune responses may
allow for more targeted use depending on the stage and type of disease.
It has recently been speculated that the ability of corticosteroids to
selectively inhibit type 1 cytokine responses would lead to enhancement
of Th2 responses (24). Thus, in the case of allergic or asthmatic
disease, it is possible that prolonged treatment could potentiate
ongoing Th2 responses (35). This concept, however, must be viewed in
light of the fact that steroids prevent eosinophil accumulation.
Moreover, in a study of BAL cells from asthmatic patients, it was shown
that steroid-sensitive asthmatics had a decrease in the number of BAL
cells expressing IL-4 or IL-5 mRNA with a rise in the number of cells
expressing IFN- (36). In the same study, steroid-resistant patients
had a reduction in the number of BAL cells expressing IFN- following
steroid treatment. Overall, while the mechanism by which
corticosteroids affect Th1 and Th2 responses is not entirely clear,
they remain the best treatment for treating the symptoms of acute
allergic and asthmatic disease. The real question will be whether
corticosteroids can be reserved for treatment for acute disease, while
various immune manipulations (i.e., cytokine treatment, altered T cell
ligands, DNA) can alter established Th2 responses, leading to a change
in the underlying cause of the disease. Finally, the ability of
steroids to inhibit both IL-12 production and responsiveness may be
related to some of their effectiveness in treating autoimmune diseases
in which IL-12 has a role.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: DXM, dexamethasone; PGE2, prostaglandin E2; 8-Br-cAMP, 8-bromoadenosine 3:5 cyclic monophosphate; MFI, mean fluorescence intensity; PE, phycoerythrin.
Received for publication April 1, 1998. Accepted for publication May 12, 1998.
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E. Kuroda and U. Yamashita Mechanisms of Enhanced Macrophage-Mediated Prostaglandin E2 Production and Its Suppressive Role in Th1 Activation in Th2-Dominant BALB/c Mice J. Immunol., January 15, 2003; 170(2): 757 - 764. [Abstract] [Full Text] [PDF]
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 J. Li, U. M. Padigel, P. Scott, and J. P. Farrell Combined Treatment with Interleukin-12 and Indomethacin Promotes Increased Resistance in BALB/c Mice with Established Leishmania major Infections Infect. Immun., October 1, 2002; 70(10): 5715 - 5720. [Abstract] [Full Text] [PDF]
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 L. Walch and P. L. Morris Cyclooxygenase 2 Pathway Mediates IL-1{beta} Regulation of IL-1{alpha}, -1{beta}, and IL-6 mRNA Levels in Leydig Cell Progenitors Endocrinology, September 1, 2002; 143(9): 3276 - 3283. [Abstract] [Full Text] [PDF]
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S. T. Ahmed, A. Mayer, J.-D. Ji, and L. B. Ivashkiv Inhibition of IL-6 signaling by a p38-dependent pathway occurs in the absence of new protein synthesis J. Leukoc. Biol., July 1, 2002; 72(1): 154 - 162. [Abstract] [Full Text] [PDF]
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D. Franchimont, J. Galon, M. S. Vacchio, S. Fan, R. Visconti, D. M. Frucht, V. Geenen, G. P. Chrousos, J. D. Ashwell, and J. J. O'Shea Positive Effects of Glucocorticoids on T Cell Function by Up-Regulation of IL-7 Receptor {alpha} J. Immunol., March 1, 2002; 168(5): 2212 - 2218. [Abstract] [Full Text] [PDF]
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S. S. SALVI, K. SURESH BABU, and S. T. HOLGATE Is Asthma Really Due to a Polarized T Cell Response Toward a Helper T Cell Type 2 Phenotype? Am. J. Respir. Crit. Care Med., October 15, 2001; 164(8): 1343 - 1346. [Full Text] [PDF]
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 K. Qadir, A. Metwali, A. M. Blum, J. Li, D. E. Elliott, and J. V. Weinstock TGF-beta and IL-10 regulation of IFN-gamma produced in Th2-type schistosome granulomas requires IL-12 Am J Physiol Gastrointest Liver Physiol, October 1, 2001; 281(4): G940 - G946. [Abstract] [Full Text] [PDF]
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S. Latour, H. Tanaka, C. Demeure, V. Mateo, M. Rubio, E. J. Brown, C. Maliszewski, F. P. Lindberg, A. Oldenborg, A. Ullrich, et al. Bidirectional Negative Regulation of Human T and Dendritic Cells by CD47 and Its Cognate Receptor Signal-Regulator Protein-{alpha}: Down-Regulation of IL-12 Responsiveness and Inhibition of Dendritic Cell Activation J. Immunol., September 1, 2001; 167(5): 2547 - 2554. [Abstract] [Full Text] [PDF]
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 Y. Chen, J. Zhang, S. A. Moore, Z. K. Ballas, J. P. Portanova, A. M. Krieg, and D. J. Berg CpG DNA induces cyclooxygenase-2 expression and prostaglandin production Int. Immunol., August 1, 2001; 13(8): 1013 - 1020. [Abstract] [Full Text] [PDF]
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 P. Kalinski, P. L. Vieira, J. H. N. Schuitemaker, E. C. de Jong, and M. L. Kapsenberg Prostaglandin E2 is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer Blood, June 1, 2001; 97(11): 3466 - 3469. [Abstract] [Full Text] [PDF]
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R. D. Newberry, J. S. McDonough, W. F. Stenson, and R. G. Lorenz Spontaneous and Continuous Cyclooxygenase-2-Dependent Prostaglandin E2 Production by Stromal Cells in the Murine Small Intestine Lamina Propria: Directing the Tone of the Intestinal Immune Response J. Immunol., April 1, 2001; 166(7): 4465 - 4472. [Abstract] [Full Text] [PDF]
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D. J. Berg, J. Zhang, D. M. Lauricella, and S. A. Moore IL-10 Is a Central Regulator of Cyclooxygenase-2 Expression and Prostaglandin Production J. Immunol., February 15, 2001; 166(4): 2674 - 2680. [Abstract] [Full Text] [PDF]
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E. Kuroda, T. Sugiura, K. Okada, K. Zeki, and U. Yamashita Prostaglandin E2 Up-Regulates Macrophage-Derived Chemokine Production but Suppresses IFN-Inducible Protein-10 Production by APC J. Immunol., February 1, 2001; 166(3): 1650 - 1658. [Abstract] [Full Text] [PDF]
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P. C. Joshi, X. Zhou, M. Cuchens, and Q. Jones Prostaglandin E2 Suppressed IL-15-Mediated Human NK Cell Function Through Down-Regulation of Common {{gamma}}-Chain J. Immunol., January 15, 2001; 166(2): 885 - 891. [Abstract] [Full Text] [PDF]
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 C. A Dinarello Targeting interleukin 18 with interleukin 18 binding protein Ann Rheum Dis, November 1, 2000; 59(90001): i17 - 20. [Abstract] [Full Text] [PDF]
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M.-N. Avice, M. Rubio, M. Sergerie, G. Delespesse, and M. Sarfati CD47 Ligation Selectively Inhibits the Development of Human Naive T Cells into Th1 Effectors J. Immunol., October 15, 2000; 165(8): 4624 - 4631. [Abstract] [Full Text] [PDF]
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D. E. Jones, L. U. Buxbaum, and P. Scott IL-4-Independent Inhibition of IL-12 Responsiveness During Leishmania amazonensis Infection J. Immunol., July 1, 2000; 165(1): 364 - 372. [Abstract] [Full Text] [PDF]
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T. W. Klein, C. A. Newton, N. Nakachi, and H. Friedman {Delta}9-Tetrahydrocannabinol Treatment Suppresses Immunity and Early IFN-{gamma}, IL-12, and IL-12 Receptor {beta}2 Responses to Legionella pneumophila Infection J. Immunol., June 15, 2000; 164(12): 6461 - 6466. [Abstract] [Full Text] [PDF]
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E. Kuroda, T. Sugiura, K. Zeki, Y. Yoshida, and U. Yamashita Sensitivity Difference to the Suppressive Effect of Prostaglandin E2 Among Mouse Strains: A Possible Mechanism to Polarize Th2 Type Response in BALB/c Mice J. Immunol., March 1, 2000; 164(5): 2386 - 2395. [Abstract] [Full Text] [PDF]
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D. Franchimont, J. Galon, M. Gadina, R. Visconti, Y.-J. Zhou, M. Aringer, D. M. Frucht, G. P. Chrousos, and J. J. O'Shea Inhibition of Th1 Immune Response by Glucocorticoids: Dexamethasone Selectively Inhibits IL-12-Induced Stat4 Phosphorylation in T Lymphocytes J. Immunol., February 15, 2000; 164(4): 1768 - 1774. [Abstract] [Full Text] [PDF]
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 R. Harley, C. R. Helps, D. A. Harbour, T. J. Gruffydd-Jones, and M. J. Day Cytokine mRNA Expression in Lesions in Cats with Chronic Gingivostomatitis Clin. Vaccine Immunol., July 1, 1999; 6(4): 471 - 478. [Abstract] [Full Text] [PDF]
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F. Aloisi, G. Penna, E. Polazzi, L. Minghetti, and L. Adorini CD40-CD154 Interaction and IFN-{gamma} Are Required for IL-12 But Not Prostaglandin E2 Secretion by Microglia During Antigen Presentation to Th1 Cells J. Immunol., February 1, 1999; 162(3): 1384 - 1391. [Abstract] [Full Text] [PDF]
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 I-C. Ho, J. P. Arm, C. O. Bingham III, A. Choi, K. F. Austen, and L. H. Glimcher A Novel Group of Phospholipase A2s Preferentially Expressed in Type 2 Helper T Cells J. Biol. Chem., May 18, 2001; 276(21): 18321 - 18326. [Abstract] [Full Text] [PDF]
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 L. L. Reznikov, S.-H. Kim, J. Y. Westcott, J. Frishman, G. Fantuzzi, D. Novick, M. Rubinstein, and C. A. Dinarello IL-18 binding protein increases spontaneous and IL-1-induced prostaglandin production via inhibition of IFN-gamma PNAS, February 29, 2000; 97(5): 2174 - 2179. [Abstract] [Full Text] [PDF]
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