* Microbiology and Tumor Biology Center, Karolinska Institutet, and
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden
Correspondence: Dr. Hans-Gustaf Ljunggren, Microbiology and Tumor Biology Center, Karolinska Institutet, 171 77 Stockholm, Sweden. E-mail: hans-gustaf.ljunggren{at}mtc.ki.se
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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release and suppressed antigen presentation by DCs.
The same effect was observed with rolipram, a specific inhibitor of
phosphodiesterase type 4, but not with inhibitors of other
phosphodiesterases. The decreased antigen presentation by DCs was
associated with an enhanced production of interleukin (IL)-10 and with
lower major histocompatibility complex type II (MHC II) expression.
Furthermore, the inhibition of antigen presentation and MHC II
expression was significantly reversed by treatment of DCs with
neutralizing antibody against IL-10, suggesting the involvement of an
IL-10-dependent mechanism. Taken together, these results might explain
why certain cAMP-elevating agents such as rolipram are effective in
blocking autoimmunity and inflammation.
Key Words: antigen presentation • cytokines • drug inhibitors • lipopolysaccharide
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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cAMP is a cyclic nucleotide that functions as an intracellular second
messenger and can modulate the activity of various cellular processes.
Elevation of intracellular cAMP in immune cells generally leads to
suppression of inflammatory function. For example, prostaglandin
E2 (PGE2), an endogenous cAMP-elevating agent,
suppresses the release of inflammatory cytokines such as tumor necrosis
factor (TNF-), interleukin (IL)-1, and IL-6 while up-regulating
IL-10, an anti-inflammatory cytokine, from LPS-stimulated macrophages
[9
]. In DCs, the effects of cAMP-elevating agents seem
to be mixed and depend on the type of stimulation. Some studies have
demonstrated that cAMP-elevating agents such as PGE2
[10
], solambutol [11
], and cholera toxin
[12
] inhibit IL-12 (p70) production from LPS-stimulated
DCs. On the contrary, PGE2 has also been shown
to stimulate DCs and promote IL-12 production when given in combination
with TNF- [13
, 14
]. However, Kalinksi et
al. have recently reported that the augmentation of IL-12 by
PGE2 from TNF--stimulated DCs is in fact the IL-12 p40
subunit, which antagonizes the effects of the bioactive IL-12 p70
heterodimer [15
].
Although elevation of intracellular cAMP can be achieved by
PGE2, the effects are nonspecific, and this method is
generally not feasible for therapeutic use. A more specific elevation
of intracellular cAMP can be achieved through the inhibition of
phosphodiesterases (PDEs), the only known enzymes that degrade cAMP. To
date, 10 different PDE families have been identified in which PDE types
3 and 4 are the predominant isoforms found in immune cells
[16
, 17
]. The major isoform that is
expressed in macrophages is PDE type 4, and rolipram, a PDE type 4
inhibitor, has been shown to inhibit TNF- and increase IL-10
secretion in macrophages [18
]. A more recent study
performed with human blood-derived DCs shows that PDE type 3 and 4
inhibitors suppress TNF- release on LPS stimulation
[19
].
Although many studies involving cAMP have been performed on
macrophages, little has been reported on the isolated effects of cAMP
on DC function. Thus, in the present report, we sought to determine the
effects of cAMP-elevating agents and specific PDE inhibitors on mouse
DCs. We demonstrate that TNF- secretion and antigen presentation by
LPS-stimulated bone marrow-derived DCs were suppressed via cAMP and
cAMP-elevating agents. The inhibition of antigen presentation was
related to decreased MHC class II expression on DCs and was mediated
via IL-10.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell isolation and culture
Bone marrow cells were harvested from the femurs and
tibias of BALB/c mice by flushing the bones with a syringe. These cells
were resuspended in DC medium [Dulbecco’s modified eagle’s medium
supplemented with penicillin and streptomycin, L-glutamine,
15% fetal bovine serum (Integro b.v., Zaandam, Holland), and 10 ng/mL
of recombinant murine granulocyte-macrophage colony-stimulating factor
(Peprotech Inc., Rocky Hill, NJ)]. The bone marrow cells were seeded
in one 12-well plate/mouse (
3x106 cells/well) at 3 mL
per well. One milliliter of medium was removed on day 3 and replaced
with fresh DC medium. In some experiments, the bone marrow DC cultures
were further purified by sorting CD11c+ cells using the
magnetically activated cell sorting (MACS) separation system (Miltenyi
Biotech, Bergisch Gladbach, Germany).
Fluorescein-activated cell sorter (FACS) analysis
DCs were harvested on day 5, placed in fresh DC medium at a
concentration of 3 x 106 cells in 3 mL in a six-well
plate precoated with an antiadherence chemical, poly-HEME (6 mg/mL,
Sigma). Some of the cultures were stimulated with LPS (50 ng/mL) in the
presence or absence of various cAMP-elevating agents as indicated for
18 h. The DCs were then harvested, spun down, and Fc receptor
blocked in anti-CD16/CD32 monoclonal antibody hybridoma supernatant
(HB-197, clone 2.4G2) on ice for 1 h. The cells were seeded in a
96-well plate (0.5–1x106), washed, and incubated on ice
for 1 h with 50 µL of directly conjugated antibodies (0.5–1
µg). The samples were washed twice, resuspended in phosphate-buffered
saline, and analyzed by flow cytometry with a FACScan (Becton
Dickinson, Mountain View, CA) using Cellquest 3.1 software (Becton
Dickinson).
Cytokine release assays
DCs were harvested on day 5 and placed in fresh DC medium at a
concentration of 3 x 106 cells in 3 mL, in a six-well
plate. The DCs were then treated with LPS (50 ng/mL) in the presence or
absence of various cAMP-elevating agents for 18 h as indicated
below. Cell-free supernatants were collected from the DC cultures, and
the TNF- and IL-10 contents were measured by commercial
enzyme-linked immunosorbent assay (ELISA) kits (PharMingen).
CD4+ T cell proliferation assay
On day 5 of culture, the indicated treatments were added to
2 x 104 DCs and at the same time cells were pulsed
with 1 µg/mL of OVA323-339 peptide (Interactiva, Ulm,
Germany) in U bottom 96-well tissue culture plates. On day 7, the DCs
were washed three times in DC medium and cocultured with 6 x
104 naive OVA-specific I-Ad-restricted
CD4+ DO11.10 T cells purified from spleens of DO11.10 mice
with CD4 (L3T4) MACS beads (Miltenyi Biotech). Cultures for the
proliferation assay were incubated for 72 h and
[3H]thymidine (1 µCi/mL) was added for the last 8 h of the assay. The plates were harvested on glass fiber filters
(Wallac Oy, Turku, Finland) and analyzed in a ß-scintillation counter
(Wallac Oy).
Measurement of cAMP and cGMP in DCs
CD11c+ cells were sorted from bone marrow DC
cultures using the MACS separation system (Miltenyi Biotech) on day 5
of culture. Cells (105) were seeded in 96-well round-bottom
tissue culture plates and treated as indicated for 1.5 h. The
cells were lysed and intracellular cAMP and cGMP were measured using
commercial enzyme immunoassay kits (Amersham-Pharmacia Biotech,
Upsalla, Sweden).
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
and augmented IL-10
release from LPS-stimulated DCs and increase IL-10 release from mouse peritoneal
macrophages [9
, 18
]. To examine whether
similar effects are found on DCs, TNF- and IL-10 releases were
measured from bone marrow-derived DCs stimulated with LPS for 18 h
in the presence of various cAMP-elevating agents. In a dose-dependent
manner, the release of TNF- was inhibited and IL-10 was augmented by
8-Br-cAMP, PGE2, and 3-isobutyl-1-methylxanthine (IBMX), a
nonselective PDE inhibitor (Fig. 1 A
B
). Thus, concerning cytokine production, the DC response to
cAMP was similar to that previously observed with mouse peritoneal
macrophages.
 View larger version (38K): [in a new window] |
Figure 1. 8-Br-cAMP, IBMX, PGE2, and rolipram inhibition of TNF-
and augmentation of IL-10 release from LPS-stimulated DCs. Bone
marrow-derived DCs were treated with LPS (50 ng/mL) in the presence or
absence of various concentrations of 8-Br-cAMP, IBMX, PGE2,
and specific PDE inhibitors as indicated. Cell-free supernatants were
harvested 18 h later and the (A and C) TNF- and (B and D) IL-10
contents were measured by ELISA. Results are expressed as mean ±
SD of triplicate determinations of duplicate cultures. *,
P < 0.01 compared with controls.
|
inhibition and IL-10
augmentation was regulated by a rolipram-sensitive PDE in DCs and augmentation of IL-10 by DCs was examined. In a
dose-dependent manner, TNF- release was significantly inhibited, and
IL-10 release was augmented by rolipram (PDE type 4 inhibitor) but not
by 8-methoxymethyl-IBMX (8MM-IBMX) (PDE type I inhibitor) or quazinone
(PDE type 3 inhibitor) (Fig. 1C
1D)
. In some experiments, cilostamide,
another PDE type 3 inhibitor, was used, and results similar to those
with quazinone were obtained (data not shown). Next, the ability of
these PDE inhibitors to elevate intracellular cAMP in DCs was examined.
Addition of rolipram and IBMX significantly increased intracellular
cAMP levels in DCs, whereas 8MM-IBMX and quazinone had no effect
(Table 1 ). On the contrary, none of the PDE inhibitors affected
intracellular cGMP levels, excluding any involvement of cGMP. Moreover,
the addition of 8-Br-cGMP did not inhibit LPS-induced cytokine
production by DCs (data not shown). Taken together, these results
suggest the involvement of a rolipram-sensitive PDE type 4 in
regulating the cAMP pool leading to TNF- inhibition and IL-10
augmentation in LPS-stimulated DCs. |
View this table: [in a new window] |
Table 1. Measurement of Intracellular cAMP and cGMP in DCs after Treatment with
Various PDE Inhibitors
|
 View larger version (29K): [in a new window] |
Figure 2. The effect of cAMP-elevating agents on IL-10 release from poly
I:C-stimulated DCs. Bone marrow-derived DCs were treated with poly I:C
(70 µg/mL) in the presence or absence of various concentrations of
cAMP-elevating agents. Cell-free supernatants were harvested 18 h
later, and the IL-10 content was measured by ELISA. Results are
expressed as means ± SD of triplicate determinations
of duplicate cultures. *, P < 0.01 compared with lane
2.
|
 View larger version (29K): [in a new window] |
Figure 3. 8-Br-cAMP, IBMX, PGE2, and rolipram inhibition of antigen
presentation by DCs. Bone marrow-derived DCs were seeded in 96-well
plates, pulsed with 1 µg/mL of OVA323-339 peptide, and
treated with LPS (50 ng/mL) and various concentrations of 8-Br-cAMP,
IBMX, PGE2, and specific PDE inhibitors as
indicated, for 2 days. The DCs were washed three times and cocultured
with purified naive OVA peptide-specific CD4+ DO11.10 T
cells. Proliferation of T cells was measured by thymidine uptake 3 days
later. The thymidine uptake (counts per minute) of T cells primed by
DCs treated with 1 µg/mL of OVA323-339 peptide alone was
subtracted from each of the values. Results are expressed as mean
percentages of control (DCs treated with LPS and 1 µg/mL of
OVA323-339 alone) ± SD of triplicate
cultures. *, P < 0.01 compared with DCs treated with
LPS alone.
|
 View larger version (20K): [in a new window] |
Figure 4. 8-Br-cAMP inhibition of the LPS-induced up-regulation of MHC class II
expression on DCs. DCs (3 x106) were left untreated or
treated with LPS (50 ng/mL), LPS + anti-IL-10 (10 µg/mL),
LPS + cAMP (200 µM), or LPS + cAMP + anti-IL-10 in
12-well tissue culture plates. After an 18-h incubation, cell surface
expression of MHC class II was analyzed on CD11c+ cells.
The number in each histogram plot represents the percentage of cells
within the MHC class II high region. The data shown are representative
of four independent experiments.
|
|
View this table: [in a new window] |
Table 2. Effect of cAMP-Elevating Agents on the Expression of MHC Class II,
CD40, CD80, and CD86 by LPS-Stimulated
DCsa
|
 View larger version (27K): [in a new window] |
Figure 5. Peptide concentration-dependent inhibition of antigen presentation by
rolipram. Bone marrow-derived DCs were seeded in 96-well plates, pulsed
with various concentrations of OVA323-339 peptide as
indicated, and treated with or without LPS (50 ng/mL) in the presence
or absence of rolipram (10 µM) for 2 days. The DCs were washed three
times and cocultured with purified naive OVA peptide-specific
CD4+ DO11.10 T cells. Proliferation of T cells was measured
by thymidine uptake 3 days later. Results are expressed as mean counts
per minute ± SD of triplicate cultures. *,
P < 0.01 compared with DCs treated with LPS alone at
the respective peptide concentrations.
|
and
augmented IL-10 release (Fig. 6 A
B
). Furthermore, a DC-T cell titration curve was generated using
the CD11c+ DCs. As shown in Figure 6C , rolipram
significantly inhibited LPS-induced up-regulation of antigen
presentation by DCs at all DC-T cell ratios except at the 3:1 ratio.
Taken together, these experiments suggest that cAMP-elevating agents
affect DC function directly and that their effects are not mediated by
non-DC contaminants.
 View larger version (18K): [in a new window] |
Figure 6. Effects of cAMP-elevating agents on cytokine production and antigen
presentation by CD11c+ cells sorted from bone
marrow-derived DC cultures. CD11c+ cells
(2 x105) were seeded in 12-well tissue culture plates
with the indicated treatments for 18 h. The cell-free supernatants
were harvested and (A) TNF- and (B) IL-10 contents were measured by
ELISA. Results are expressed as means ± SD of
determinations of duplicate cultures. (C) 6.0 x 104,
2.0 x 104, 0.66 x 104, or 0.33 x 104 CD11c+ cells were seeded in 96-well
plates, pulsed with 1 µg/mL of OVA323-339 peptide, and
treated with or without LPS (50 ng/mL) in the presence or absence of
rolipram (10 µM) as indicated, for 2 days. The DCs were washed three
times and cocultured with 2.0 x 104 purified naive
OVA peptide-specific CD4+ DO11.10 T cells. Proliferation of
T cells was measured by thymidine uptake 3 days later. Results are
expressed as mean counts per minute (CPM) ± SD of
triplicate cultures. *, P < 0.01 compared with DCs
treated with LPS alone at the respective DC-T cell ratio.
|
release (Fig. 7B)
or CD40 expression by any
of these agents (Table 2)
. Taken together, these data suggest that
there are both IL-10-dependent and -independent effects of
cAMP-elevating agents on DCs.
 View larger version (26K): [in a new window] |
Figure 7. Anti-IL-10 antibody reverses cAMP-induced inhibition of antigen
presentation but not TNF- release by DCs. (A) Bone marrow-derived
DCs were seeded in 96-well plates, pulsed with 1 µg/mL of
OVA323-339 peptide, and treated with LPS (50 ng/mL), the
indicated compounds, and antibody for 2 days. The DCs were washed three
times and cocultured with purified naive OVA peptide-specific
CD4+ DO11.10 T cells. Proliferation of T cells was measured
by thymidine uptake 3 days later. The thymidine uptake [counts per
minute (CPM)] of T cells primed by DCs treated with 1 µg/mL of
OVA323-339 peptide alone was subtracted from each of the
values. Results are expressed as mean counts per minute ±
SD of triplicate cultures. *, P < 0.01
compared with DCs treated with the same compound but with Rat
IgG1 isotype control antibody. (B) 106 DCs were
seeded in 12-well tissue culture plates with the indicated treatments
for 18 h. The cell-free supernatants were harvested, and TNF-
content was measured by ELISA. Results are expressed as means ±
SD of duplicate determinations of duplicate cultures.
|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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secretion and
antigen presentation by bone marrow-derived DCs were suppressed by cAMP
and cAMP-elevating agents. Particular inhibitory effects of
cAMP-elevating agents on DCs were mediated via IL-10. First, all
cAMP-elevating agents augmented the release of IL-10 from
LPS-stimulated DCs. Second, neutralization of IL-10 by anti-IL-10
antibody reversed the inhibition of antigen presentation and MHC class
II expression by these compounds. It is interesting that not all
effects of cAMP-elevating agents were mediated via IL-10. The
inhibition of TNF- release and down-regulation of CD40 expression
were unaffected by anti-IL-10 antibody. This was surprising, because
anti-IL-10 antibody reverses cAMP-mediated TNF- inhibition by
LPS-stimulated macrophages [9
]. Thus, the effects of
cAMP on macrophages and DCs seem functionally distinct. The inhibition of antigen presentation by 8-Br-cAMP, PGE2, IBMX, and rolipram might result from suppression of the LPS-induced up-regulation of MHC class II expression. The block in MHC class II up-regulation and the inhibition of proliferation could both be reversed by adding anti-IL-10 antibody. These data suggest that the inhibition of antigen presentation was partly due to reduced MHC class II expression. Although these compounds also blocked the up-regulation of CD40 expression by LPS, CD40 was probably not involved because anti-IL-10 antibody could not restore its expression. In addition, the involvement of costimulatory molecules was unlikely, because these compounds do not inhibit the expression of CD80 or CD86.
We also tested the effects of several specific PDE inhibitors on the
augmentation of IL-10 and inhibition of antigen presentation. A recent
study performed in human blood-derived DCs showed that PDE type 3 and 4
inhibitors suppress TNF- release on LPS stimulation. In our present
study using mouse bone marrow-derived DCs, only the inhibitors specific
for PDE type 4 (rolipram) inhibited TNF- release and antigen
presentation by DCs. Similar to cAMP and PGE2, rolipram
augmented IL-10 production from LPS-stimulated DCs, and some of the
inhibitory effects of rolipram were reversed by anti-IL-10 antibody.
Furthermore, rolipram but not 8MM-IBMX or quazinone increased
intracellular cAMP levels in DCs. Taken together, these data strongly
suggest the involvement of rolipram-sensitive PDE type 4 in regulating
cAMP levels of DCs and in the subsequent inhibition of DC function
through up-regulation of IL-10.
The therapeutic potential for cAMP-elevating agents, especially PDE
inhibitors, for autoimmune and inflammatory disorders has gathered
considerable interest. Since these compounds have been reported to
increase IL-10 and inhibit TNF- and IL-12 production, it has been
proposed that the drugs shift the immune response towards a Th2
phenotype. Autoimmune disease models which are Th1-mediated such as EAE
[21
, 22
] and collagen-induced arthritis
[23
, 24
] have been successfully treated
with PDE type 3 and 4 inhibitors. On the contrary, studies performed
with asthmatic and atopic models have revealed opposite effects
[25
26
27
]. In these studies, a preferential inhibition of
Th2 rather than Th1 responses was observed. This discrepancy might be
explained by our data presented here because we demonstrate that the
overall CD4+ T cell response was down-regulated by cAMP and
PDE inhibitors. Thus, cAMP-elevating agents might inhibit both Th1 and
Th2 responses because they cause an overall suppression of MHC class II
antigen presentation. This could also be true for CD8+ T
cell responses, because MHC class I expression was also down-regulated
by these compounds (data not shown). In addition, the inhibition of
TNF- by PDE inhibitors has been thought to be particularly important
in these autoimmune models. This is relevant to our present study,
because DCs might be an important source of TNF- in response to, for
example, CD40 stimulation by activated T cells during antigen
presentation. Thus, the inhibition of TNF- release from DCs by
cAMP-elevating agents might also explain some of its mechanisms of
action.
In most of our experiments, a peptide concentration of 1 µM was used
to test the proliferative response of T cells, because this
concentration yielded strong proliferation and good resolution.
However, rolipram exhibited only an intermediate degree of inhibition
at this peptide concentration (
50% inhibition), whereas at lower
peptide concentrations, the inhibition by rolipram was complete (Fig. 5) . Under physiological situations, DCs would probably encounter and
present antigens at peptide concentrations much lower than 1 µM.
Perhaps, concentrations of 0.01 µM would be more likely to mimic in
vivo situations, because naive T cells proliferated only in response to
LPS-stimulated DCs but not in response to unstimulated DCs at this
peptide concentration (Fig. 5)
. Thus, we believe that the in vivo
effects of rolipram and other cAMP-elevating agents on DCs could be
substantial under physiological conditions.
In summary, we have demonstrated that TNF- secretion and antigen
presentation by LPS-stimulated bone marrow-derived DCs were inhibited
by cAMP and cAMP-elevating agents. The inhibition of antigen
presentation but not TNF- secretion was mediated via augmentation of
IL-10 release by DCs. Furthermore, the regulation of cAMP leading to
enhanced IL-10 production in bone marrow-derived DCs occurred through a
rolipram-sensitive PDE type 4. Taken together, these results might have
important therapeutic implications because DCs play a central role in
mediating immune responses.
ke Wiberg Foundation, the Alex and Eva Wallström
Foundation, and the Lars Hiertas Foundation. We thank Dr. D. Loh for
providing us with the DO11.10 TCR-transgenic strain. We also thank
members of the H.G. Ljunggren laboratory for fruitful discussions. Received April 23, 2001; revised August 4, 2001; accepted August 6, 2001.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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