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(Received for publication, October 3,
1994; and in revised form, December 9, 1994) From the
Interleukin-13 (IL-13), a novel cytokine produced by activated
lymphocytes modulates some monocyte functions, but no data is available
concerning the signal transduction pathway. We show here, the
inhibitory effect of IL-13 on
12-O-tetradecanoylphorbol-13-acetate (TPA)-triggered reactive
oxygen intermediate production in human monocytes and the signals
involved in this response. Our results show that IL-13 produces rapid
and transient phosphoinositide hydrolysis and intracellular
Ca
Interleukin 13 (IL-13) ( However, the effect of IL-13 on the reactive oxygen
intermediates (ROI) production, an important function of monocytes that
are involved in infectious and inflammatory processes, has not yet been
investigated. The NADPH-oxidase system is the key step in the
regulation of ROI generation. The oxidase is normally dormant in
resting phagocytes, but it can be rapidly activated by a number of
stimuli such as protein kinase C agonists like phorbol esters,
12-O-tetradecanoylphorbol-13-acetate (TPA). It is known that
the oxidase requires interaction at the plasma membrane level between
membrane and cytosolic components, these include flavocytochrome b While several studies have been oriented
toward phosphorylation and activation of respiratory burst, the
reversal of the event by dephosphorylation and inactivation of the
active phagocyte to the normal resting state have not been fully
elucidated. Agents that increase the intracellular concentration of
cAMP have been shown to be negative modulators of TPA-triggered
respiratory burst in polymorphonuclear leukocytes (14) and in
Ehrlich ascites tumor cells (15) . The regulation of
intracellular cAMP level involves at least two independent systems, a G
protein pathway coupled with adenylate cyclase and the direct
activation of catalytic subunits of adenylate cyclase. In particular,
the Ca In this study, we investigate
the capacity of IL-13 to modulate respiratory burst in human monocytes
and the signaling pathways used by the cytokine to modify this
function. Our findings indicate that IL-13 inhibits TPA-triggered ROI
production by a mechanism involving a rapid and transient phospholipase
C-dependent Ca
Figure 1:
Effect of IL-13
pretreatment on TPA-triggered oxidative burst in human monocytes. The
generation of CL was monitored after TPA (100 nM) (a), IL-13 (100 ng/ml) (d), Hanks' balanced
solution (control) (e), or IL-13/anti-IL-13 antiserum complex (f) addition at time 0, as described under ``Experimental
Procedures.'' In parallel experiments, monocytes were incubated
for 5 min before TPA with IL-13 (100 ng/ml) (c) or
IL-13/anti-IL-13 antiserum complex (b). The curves are
representative of three separate experiments, each performed in
triplicate.
Figure 2:
Effect of IL-13 pretreatment on
TPA-triggered chemiluminescence production in human monocytes in the
absence (0Ca
To investigate the possible
involvement of the cAMP-dependent protein kinase pathway in the
inhibitory effect of IL-13 on TPA-triggered ROI production, cells were
preincubated with We also investigated Ca
Figure 3:
Time
course of cAMP accumulation induced by IL-13 in human monocytes.
Monocytes were incubated with (
Figure 4:
Time
course of IL-13-stimulated inositol phosphate formation in human
monocytes. Monocytes were labeled with myo-[2-
Figure 5:
Kinetics of
[Ca
In the present study we determine the initial events induced
by IL-13, which can regulate the protein kinase C-triggered respiratory
burst in human monocytes. Classically, the activation of protein kinase
C by TPA results in the activation of NADPH-oxidase, inducing the
so-called respiratory burst(26, 27, 28) .
Probably, phosphorylation of cytosolic oxidase proteins, p47 and p67 by
activated protein kinase C is a key step in this
response(11, 13) . ROI and proinflammatory
cytokines are likely to be involved in phagocyte antimicrobial activity
and inflammatory responses. IL-13 produced by activated Th-2 cells is
described to suppress the production of proinflammatory
monokines(1, 6) . However, no information is available
on the action of IL-13 on human ROI production. Our results
demonstrate that IL-13 inhibits the TPA-induced oxidative burst in
human monocytes when added 5 min before TPA and also for longer periods
up to 18 h (data not shown). The nonspecific inhibition of ROI
production is excluded since in the presence of anti-IL-13 antiserum
the effect of IL-13 is cancelled. The IL-13 down-modulatory effect on
human monocyte oxidative burst supports that described with another
anti-inflammatory cytokine, IL-4. Indeed, preexposure of human
monocytes to IL-4 for 24 h decreases the respiratory burst induced by
TPA(29) . IL-4 also inhibits this response when other stimuli
such as zymosan, platelet-activating factor, chemotactic peptide and
IFN- Having established that IL-13 induces an inhibitory effect
on ROI production, we investigated the signal transduction pathways
used by this cytokine to induce the deactivation of the ROI response.
In leukocytes, agents which increase intracellular cAMP concentrations
(prostaglandins E Different studies show that the accumulation of cAMP can
be subsequent to intracellular Ca It was of interest to
verify the capacity of IL-13 to promote phospholipase C activation and
intracellular Ca Otherwise, we relate
these initial events induced by IL-13 to the inhibition of the human
monocyte biological response, the oxidative burst. Indeed, in the
presence of TMB8 and neomycin sulfate, this inhibitory effect of IL-13
is impaired, whereas, in the absence of extracellular Ca In conclusion, we describe here
for the first time the initial steps in the signaling pathway of IL-13
related to respiratory burst decrease. Indeed, direct measurement of
second messengers and the use of metabolic inhibitors allowed us to
establish a temporal sequence and a link between
InsP
Volume 270,
Number 10,
Issue of March 10, 1995 pp. 5084-5088
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
ROLE OF CALCIUM AND CYCLIC AMP (*)
mobilization. Furthermore, IL-13 induces
intracellular cAMP accumulation through inositol
1,4,5-trisphosphate-dependent Ca mobilization.
Metabolic inhibitors were used to relate the first steps in signaling
pathways to the inhibitory effect of IL-13 on TPA-triggered reactive
oxygen intermediate production. Indeed, inhibitors of phospholipase C
(neomycin), intracellular Ca mobilization
(8-[N,N-diethylamino]-octyl
3,4,5-trimethoxybenzoate hydrochloride), adenylate cyclase
(
-tetrahydrocannabinol), and protein kinase A (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide)
impair the IL-13 inhibitory response. Altogether these observations
indicate that modulatory effect of IL-13 on the TPA-induced oxidative
burst is the result of the intracellular cAMP accumulation through an
inositol 1,4,5-trisphosphate-induced Ca
mobilization-dependent pathway.
)is a novel lymphokine of 112
amino acids with a molecular mass of 12.5 kDa produced by activated
Th-2 cells(1) . This cytokine induces cell surface phenotype
changes and displays immunomodulatory effects on B cells and human
monocytes ( (2) and for reviewed, see (3) ). In B
cells, IL-13 induces proliferation and differentiation(4) ,
promotes CD23 expression and the production of certain immunoglobulin
isotypes such as IgG4 and IgE(5) . IL-13 displays many effects
on monocytes. It induces morphological changes (2) and enhances
the expression of several members of the integrin superfamily and class
II major histocompatibility complex antigens, whereas it down-regulates
the expression of CD14 and Fc
R receptors (CD64, CD32, and
CD16)(6) . IL-13 inhibits immunodeficiency virus type 1
production, but the precise mechanism remains to be
elucidated(7, 8) . It reduces pyrogen-induced
expression of procoagulant activity(9) . In
lipopolysaccharide-stimulated monocytes(1, 6) , IL-13
inhibits the production of chemokines (IL-8, macrophage inflammatory
proteins 1
), hematopoietic growth factors (granulocyte/macrophage
colony-stimulating factor, granulocyte colony-stimulating factor), and
proinflammatory cytokines (e.g. tumor necrosis factor ,
IL-1, IL-6). Thus, IL-13 is considered as an anti-inflammatory
cytokine.
, the cytosolic proteins p47 and p67, and the
small GTP-binding proteins Rap1A, Rac-1, and Rac-2 (for review, see (10, 11, 12) ). Classically, protein kinase C
phosphorylates specific proteins (p47, p67) that constitute the
predominant regulatory mechanism governing the activation of the
oxidase(13) .-calmodulin complex can activate specific I and
III adenylate cyclase isozymes(16) . A coupling of
phospholipase C and adenylate cyclase effector systems through
Ca has also been reported in
leukocytes(17, 18) . mobilization and the consequent
protein kinase A activation.
Materials
Purified recombinant human IL-13
(IL-13) was produced in transformed Chinese hamster ovary cells and
purified as described before(1) . As optimal responses were
obtained with 100 ng/ml, this concentration of IL-13 was used in all
the experiments described. The lipopolysaccharide concentration
(measured by Limulusamoebocyte lysate assay) was
always less than 30 pg/µg of protein. The neutralizing anti-IL-13
antiserum was obtained in rabbits using the purified recombinant
cytokine as immunogen. Briefly, 50 µg of IL-13 dissolved in 0.5 ml
of saline and emulsified with an equal volume of Freund's
complete adjuvant were injected subcutaneously. Two, three, and four
weeks after the first immunization, the same amount of IL-13 was
injected in Freund's incomplete adjuvant. Rabbits were bled at
the same time, and the titers of the antisera were followed by
radioimmunoassay as described before (19) using an iodinated
IL-13 as tracer. (
)Special for macrophages medium, RPMI
1640, inositol-free RPMI 1640, fetal calf serum, and Hanks'
balanced salt solution with or without Ca were from
Life Technologies, Inc. myo-[2-
H]Inositol, D-myo-[2-H]inositol
1-phosphate, D-myo-[2-H]inositol
1,4-bisphosphate, D-myo-[2-H]inositol
1,4,5-trisphosphate, D-myo-[2-H]inositol
1,3,4,5-tetrakisphosphate, and complete phase-combining system liquid
scintillant were from Amersham Corp.
12-O-Tetradecanoylphorbol-13-acetate (TPA),
8-[N,N-diethylamino]-octyl
3,4,5-trimethoxybenzoate hydrochloride (TMB8), forskolin, N
,2`-O-dibutyryladenosine 3`:5`-cyclic
monophosphate (dibutyryl cAMP), 1-isobutyl-3-methylxanthine,
-tetrahydrocannabinol (-THC),
neomycin sulfate, and indomethacin were from Sigma, and Fluo
3-acetoxymethylester (Fluo 3-AM) was from Molecular Probes (Eugene,
OR). N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide
(H89) was from France Biochem, Meudon, France. All other chemicals and
solvents were reagent grade.Cell Isolation
Peripheral blood mononuclear cells
were separated by a standard Ficoll-Hypaque (MSL, Eurobio, Les Ullis,
France) gradient method. Human monocytes were isolated from human
peripheral blood mononuclear cells by adherence to plastic for 2 h in
special for macrophages medium, supplemented with 5% fetal calf serum,
2 mML-glutamine, and antibiotics, at 37 °C in a
humidified atmosphere containing 5% CO. Nonadherent cells
were removed by washing, and remaining adherent cells (monocytes purity
was >95%) were cultured overnight. They were designated as monocytes
according to CD14 antigen expression and nonspecific esterase
staining(20) .Assay of ROI Production
Peripheral blood
mononuclear cells (6 
10
/assay) were seeded into
luminometer sterile cuvettes, and ROI production was measured by
chemiluminescence (CL) in the presence of luminol (60 µM),
using a thermostatically (37 °C) controlled luminometer 1251 LKB as
described previously (21) . The generation of CL in human
monocytes triggered with 100 nM TPA (time 0) was continuously
monitored for 10 min, and the area under the curve (expressed in mV/s)
was statistically analyzed using a Hewlett Packard 85 computer.
Experiments were performed in Hanks' balanced salt solution
medium with or without Ca. In some experiments, cells
were incubated for 10 min before TPA in the presence of metabolic
inhibitors such as -THC (1 µM), an
inhibitor of adenylate cyclase, H89 (10 µM), an inhibitor
of protein kinase A, neomycin sulfate (10 µM), an
inhibitor of phospholipase C, TMB8 (10 µM), an inhibitor
of InsP
induced calcium release from intracytoplasmic
stores, and indomethacin (0.5 µM), an inhibitor of the
cyclooxygenase pathway. In all cases IL-13 or vehicle (Hanks'
balanced salt solution) was added 5 min before TPA. In parallel
experiments, IL-13/anti-IL-13 antiserum complex was used alone at time
0 or added 5 min before TPA.Measurements of [
Peripheral blood mononuclear cells (4 H]Inositol
Phosphates
10/well) were seeded into 24-well culture plates. Adherent
monocytes were incubated in RPMI 1640 inositol-free medium containing
0.04% bovine serum albumin in the presence of 7 µCi of myo-[2-H]inositol/well, for 24 h at 37
°C. The cells were washed 3 times and then stimulated by IL-13. The
reaction was stopped at different times up to 5 min by the addition of
1 ml of ice-cold methanol. Extraction of
[H]inositol phosphates was performed as described
elsewhere(22) . Briefly, 2 ml of chloroform and 0.3 ml of water
were added to the methanol-treated cells in order to obtain a final
chloroform/methanol/water ratio of 2:1:0.6. The top aqueous layer was
collected, and [H]inositol phosphates were
reextracted from the chloroform/methanol phases using 0.6 ml of water.
The inositol phosphates were separated using anion exchange SAX
Amprep
minicolumn (Amersham Corp.) and, successively
eluted with ammonium formate, 0.1 M formic acid using ammonium
formate increments from 0.1 to 1.2 M. In our conditions,
[H]InsP standards, InsP,
InsP, InsP, and InsP
were eluted at
0.1, 0.4, 0.8, and 1.2 M ammonium formate, 0.1 M formic acid, respectively. Total eluate volume was mixed with
complete phase-combining system scintillant, and radioactivity was
measured using a liquid scintillation counter.Determination of Intracellular Calcium
Concentration
Intracellular calcium concentration was measured
in single cells by a video digital microscopy technique using the
fluorescent probe Fluo 3-AM. Briefly, peripheral blood mononuclear
cells (2 10 cells) were plated into 60-mm diameter
plastic culture dishes, and adherent monocyte monolayers were loaded
with 15 µM Fluo 3-AM for 1 h at 37 °C(23) .
The cells were then washed 5 times with Hanks' balanced salt
solution (with or without Ca). The time course of the
intracytosolic Ca level was recorded every 2 s for a
total period of 2 min after the addition of IL-13. In parallel assays,
cells were preincubated with 10 µM TMB8 for 10 min before
the addition of IL-13. Ionomycine (2.5 µM) was added at
the end of each experiment to assess the maximum intensity response.
Cells were visualized with an inverted microscope (Nikon Diaphot 300).
The light source was a xenon lamp XBO 100 watts (Osram, Munich,
Germany). Excitation (488 nm) and emission (525 nm) wavelengths were
selected by a XF23 filter block (Nikon). They were acquired by an
intensified camera LHESA, LH 5038-STD (Cergy Pontoise, France). Images
were digitized, and the fluorescence was analyzed using the Imstar
starwise/fluo software system (Paris, France).Measurements of cAMP Accumulation in Human
Monocytes
Peripheral blood mononuclear cells (4
10/well) were seeded into 24-well culture plates. Adherent
cells were washed twice with incubation buffer (RPMI 1640, 1 mg/ml
bovine serum albumin, 0.5 mM 1-isobutyl-3-methylxanthine) and
incubated at room temperature with IL-13 for different periods of time
(ranging from 1 to 15 min). Forskolin (10 µM) was used as
positive control. To stop the reaction, the medium was discarded, and
the cells were lysed with 95% cold ethanol. After an incubation of 5
min at 0 °C, the lysate was removed, lyophilized, and finally
dissolved in radioimmunoassay buffer(24) . cAMP was quantified
in triplicate using a cAMP 
I-labeled radioimmunoassay
system from Amersham Corp. In parallel experiments, the kinetics of
cAMP production were followed in cells preincubated for 10 min with
neomycin sulfate (0.5 mM) or TMB8 (10 µM) before
IL-13 addition.Statistical Analysis
Results are expressed as mean
± S.E. Data were analyzed by one-way analysis of variance, and
the multiple comparisons of each treatment were calculated applying the
Tukey method(25) .
IL-13 Inhibits ROI Production Induced by TPA
TPA
induces ROI production as measured by continuous CL kinetics
generation. IL-13 had no effect on the basal oxidative response of
unstimulated monocytes, whereas, when added 5 min before the protein
kinase C agonist, the cytokine produced an inhibition of TPA-triggered
ROI production (Fig. 1). The total CL emission, area under curve (Fig. 2), and CL maximum (data not shown) were both 35% lower
compared with the TPA control. Moreover, we found that IL-13 antibody
completely reversed the IL-13 inhibitory effect on oxidative burst.
IL-13/anti-IL-13 antiserum complex per se was not able to
induce ROI production (Fig. 1).
) or in the presence
of extracellular calcium and metabolic inhibitors. Total CL emission
(area under curve) was observed for 10 min after TPA (100 nM)
(&cjs2108;) or IL-13 (100 ng/ml)+TPA (&cjs2113;) stimulation with
or without (CONTROL) inhibitors as described under
``Experimental Procedures.'' When inhibitors were used,
monocytes were preincubated (10 min) with 1 µM-THC, 10 µMH89,
10 µM neomycin sulfate (NEO), 10 µMTMB8, 0.5 µM indomethacin (IND).
Data are means ± S.E. of three separate experiments, each
performed in triplicate.**, p <
0.01.
-THC, an inhibitor of adenylate
cyclase, or H89, an inhibitor of protein kinase A. The results obtained
show that these inhibitors completely block the effect of IL-13 (Fig. 2). Moreover, forskolin (10 µM), a direct
activator of adenylate cyclase, or dibutyryl cAMP (5 mM), a
cell permeable analogue of cAMP, caused 50% inhibition of ROI
production induced by TPA. These effects were reversed in the presence
of H89 (10 µM). mobilization as another candidate pathway in IL-13 modulation of
the oxidative burst. In the absence of extracellular
Ca, the effect of IL-13 on TPA-induced ROI production
was maintained. In the presence of neomycin sulfate (inhibitor of
phospholipase C) or TMB8 (inhibitor of InsP-induced
intracellular Ca release from intracysternal stores),
the IL-13 inhibitory effect was impaired, suggesting that phospholipase
C and subsequent production of InsP-induced intracellular
Ca release can be related to the inhibitory response (Fig. 2). The involvement of prostaglandin in this mechanism is
not suggested. Indeed, in the presence of indomethacin (inhibitor of
the cyclooxygenase pathway), the effect of IL-13 on TPA-triggered ROI
production was maintained.IL-13 Induces the Production of cAMP
Since cAMP
seems to be involved in the inhibitory effect of IL-13 on TPA-induced
ROI production, we measured the time course of cAMP accumulation
induced by IL-13. Results show a rapid (1 min) and significant increase
for 15 min (maximum time of experimental observation) (Fig. 3).
In parallel, forskolin (10 µM) produced a similar kinetic
of cAMP accumulation (data not shown). In order to study whether cAMP
accumulation is linked to phospholipase C activation, neomycin sulfate
and TMB8 were tested. Both inhibitors were able to block cAMP
accumulation induced by IL-13, suggesting that phospholipase C
activation and subsequent intracellular calcium release are necessary
for the pathway leading to cAMP accumulation (Fig. 3).
) or without (
) IL-13 (100
ng/ml). In parallel experiments, cells were preincubated for 10 min
with (
) neomycin sulfate (0.5 mM) or (
) TMB8 (10
µM) before IL-13 addition. cAMP was quantified as
described under ``Experimental Procedures.'' Data are means
± S.E. of three separate experiments, each performed in
triplicate. *, p < 0.05;**, p <
0.01.
Production of Inositol Phosphates by IL-13
The
finding that the effect of IL-13 on ROI and cAMP production was
reversed by neomycin suggests the involvement of phosphoinositide
hydrolysis by phospholipase C. The results shown in Fig. 4confirm this event. Indeed, a rapid (15 s for
InsP, InsP, and InsP, 30 s for
InsP), transient, and significant increase of all four
inositol phosphate metabolites was observed when adherent monocytes
prelabeled with myo-[2-H]inositol were
incubated in the presence of IL-13.
H]inositol, washed, and incubated
with (
) or without () IL-13 (100 ng/ml).
[H]inositol phosphates were measured as described
under ``Experimental Procedures.'' Data are means ±
S.E. of three separate experiments, each performed in triplicate. *, p < 0.05;**, p <
0.01.
IL-13 Induces Intracellular Ca
At the single-cell level, a significant
increase of the fluorescent Ca Mobilization signal was observed
within 30 s after the addition of IL-13 (Fig. 5A). In
the absence of extracellular Ca, the IL-13-induced
Ca response was maintained (Fig. 5B),
suggesting that this increase is essentially a consequence of
Ca release from intracysternal stores. To test this
hypothesis, similar experiments were performed in the presence of TMB8.
In these conditions, the increase of intracytosolic Ca induced by IL-13 was completely reversed (Fig. 5C).
] response in single cells after
stimulation with IL-13. Monocytes were loaded with Fluo 3-AM, and, at
the time indicated by arrows, IL-13 (100 ng/ml) was added to cells in
Hanks' balanced solution with (A) or without (B) Ca. In parallel experiments, cells were
preincubated for 10 min in the presence of 10 µM TMB8 (C) before IL-13 addition. Determination of
[Ca] was measured as described under
``Experimental Procedures.'' Records of cell responses are
representative of three separate experiments each performed in
triplicate.
are used(29, 30) . An explanation for the
similar biological activities displayed by IL-13 and IL-4 is that their
receptors share a common subunit critical for cellular signal
transduction(31) . In contrast to the finding with
human monocytes, the respiratory burst induced by TPA in murine
resident peritoneal macrophages is enhanced by murine IL-4 used under
similar experimental conditions (32) . Recent data show that
P600 (murine IL-13) and murine IL-4 are unable to modify ROI response
triggered by TPA in murine biogel-elicited macrophages(33) .
These results suggest the necessity to be cautious when extrapolating
data obtained with murine cells to the human system. As suggested for
IL-4, the role of IL-13 in host defense and inflammation can be
significant. ROI may damage various cells at high concentrations;
however, their role is important in antimicrobial activity. The partial
inhibition by IL-13 of TPA-triggered ROI production (35%) could reduce
inflammatory reactions without completely abolishing the antimicrobial
process. and E, dibutyryl cAMP,
forskolin, and 1-isobutyl-3-methylxanthine) have often been shown to
inhibit various cellular functions such as respiratory
burst(34, 35, 36) . Some authors have
recently proposed a mechanism of protein kinase A-dependent
phosphorylation and subsequent activation of a specific phosphatase.
This event results in dephosphorylation of NADPH-oxidase subunits and
thus inactivation of the enzyme(14, 15) . Our data
suggest the involvement of the cAMP-dependent protein kinase pathway in
IL-13-induced inhibition of respiratory burst. Indeed, the direct
involvement of cAMP in the IL-13 signaling pathway is demonstrated by a
sustained increase of cAMP levels after cytokine stimulation.
Furthermore, in the presence of adenylate cyclase
(-THC) and protein kinase A (H89) inhibitors, the
effect of IL-13 on ROI production is not observed. IL-13 seems to mimic
the forskolin or dibutyryl cAMP inhibitory effect on TPA-triggered ROI
production. mobilization(17, 37, 38) . Coupling of
phospholipase C and cAMP pathways through Ca was
reported in leukocytes (18, 39) and human
neuroblastoma cells(40) . A direct activation of type I and III
adenylate cyclase by Ca and calmodulin previously
described (41, 42) could be a possible mechanism. Our
experiments show that cAMP production is markedly reduced by prior
treatment of human monocytes with an inhibitor of phospholipase C
(neomycin sulfate) or an inhibitor of InsP-induced
Ca release (TMB8). These observations suggest that
IL-13 causes intracellular cAMP accumulation by
Ca-dependent processes. rise. We demonstrate here that IL-13
induces immediate and transient hydrolysis of inositol phospholipids
and a rapid increase in intracellular Ca levels
inhibited by TMB8. These results suggest that IL-13 causes
phospholipase C activation and a release of Ca from
InsP-sensitive Ca stores. The regulation
of phospholipase C is distinct for two of the known phospholipase
families, the phospholipase C-
and phospholipase C-. The
phospholipase C- family is regulated by G proteins, while
phospholipase C-1 and -2 are regulated by protein-tyrosine
kinase (for review, see (43) ). The involvement of a
protein-tyrosine kinase in the IL-13 signal transduction pathway was
strongly suggested in a recent report. Indeed, genistein (one inhibitor
of tyrosine kinase) completely blocked the IL-13-activated
IL-4-dependent nuclear transcription factor in monocytic U937
cells(44) . A study concerning the suggested activation of
phospholipase C- through tyrosine phosphorylation induced by IL-13
has already been undertaken in our laboratory. or in the presence of indomethacin (inhibitor of cyclooxygenase
pathway), IL-13 still induces a significant inhibition of ROI
production. This last observation strongly suggests that
prostaglandins, classically described to increase intracellular cAMP
levels and inhibit ROI production in activated
phagocytes(35, 37) , are not involved in IL-13
down-regulation of the biological response studied. Our results support
the involvement of InsP-dependent Ca mobilization and subsequent cAMP accumulation in the IL-13
inhibitory effect on ROI production.-dependent Ca mobilization, the cAMP
protein-kinase pathway and inhibition of the protein kinase C-triggered
respiratory burst in human monocytes pretreated with IL-13. The
modulation of this important human monocyte function strengthens the
notion that IL-13 could play a central role in the inflammatory process
without totally inhibiting the monocyte oxygen-dependent
anti-infectious capacity. Furthermore, work will be required to
evaluate if the anti-inflammatory properties of IL-13 displayed in in vitro models, could be of clinical significance in the
future for the treatment of inflammatory human diseases.
)-THC,
-tetrahydrocannabinol; H89, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide;
CL, chemiluminescence; InsP, inositol 1-phosphate;
InsP, inositol 1,4-bisphosphate; InsP, inositol
1,4,5-trisphosphate; InsP, inositol
1,3,4,5-tetrakisphosphate.)
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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 K. A. Munger, A. Montero, M. Fukunaga, S. Uda, T. Yura, E. Imai, Y. Kaneda, J. M. Valdivielso, and K. F. Badr Transfection of rat kidney with human 15-lipoxygenase suppresses inflammation and preserves function in experimental glomerulonephritis PNAS, November 9, 1999; 96(23): 13375 - 13380. [Abstract] [Full Text] [PDF]
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 E. Pinelli, N. Poux, L. Garren, B. Pipy, M. Castegnaro, D. J. Miller, and A. Pfohl-Leszkowicz Activation of mitogen-activated protein kinase by fumonisin B1 stimulates cPLA2 phosphorylation, the arachidonic acid cascade and cAMP production Carcinogenesis, September 1, 1999; 20(9): 1683 - 1688. [Abstract] [Full Text] [PDF]
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 K. M. DeFIFE, C. R. JENNEY, E. COLTON, and J. M. ANDERSON Disruption of filamentous actin inhibits human macrophage fusion FASEB J, May 1, 1999; 13(8): 823 - 832. [Abstract] [Full Text]
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V. Patella, A. Giuliano, J.-P. Bouvet, and G. Marone Endogenous Superallergen Protein Fv Induces IL-4 Secretion from Human Fc{epsilon}RI+ Cells Through Interaction with the VH3 Region of IgE J. Immunol., November 15, 1998; 161(10): 5647 - 5655. [Abstract] [Full Text] [PDF]
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S. K. Manna and B. B. Aggarwal IL-13 Suppresses TNF-Induced Activation of Nuclear Factor-{kappa}B, Activation Protein-1, and Apoptosis J. Immunol., September 15, 1998; 161(6): 2863 - 2872. [Abstract] [Full Text] [PDF]
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D. D. Donaldson, M. J. Whitters, L. J. Fitz, T. Y. Neben, H. Finnerty, S. L. Henderson, R. M. O'Hara Jr., D. R. Beier, K. J. Turner, C. R. Wood, et al. The Murine IL-13 Receptor {alpha}2: Molecular Cloning, Characterization, and Comparison with Murine IL-13 Receptor {alpha}1 J. Immunol., September 1, 1998; 161(5): 2317 - 2324. [Abstract] [Full Text] [PDF]
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 K. Wright, S. G. Ward, G. Kolios, and J. Westwick Activation of Phosphatidylinositol 3-Kinase by Interleukin-13. AN INHIBITORY SIGNAL FOR INDUCIBLE NITRIC-OXIDE SYNTHASE EXPRESSION IN EPITHELIAL CELL LINE HT-29 J. Biol. Chem., May 9, 1997; 272(19): 12626 - 12633. [Abstract] [Full Text] [PDF]
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C. Bureau, J. Bernad, N. Chaouche, C. Orfila, M. Beraud, C. Gonindard, L. Alric, J.-P. Vinel, and B. Pipy Nonstructural 3 Protein of Hepatitis C Virus Triggers an Oxidative Burst in Human Monocytes via Activation of NADPH Oxidase J. Biol. Chem., June 15, 2001; 276(25): 23077 - 23083. [Abstract] [Full Text] [PDF]
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