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*
GSF-National Research Center for Environment and Health, Institute of Experimental Hematology, München, Germany;
Institute of Immunology, Johannes Gutenberg University Mainz, Mainz, Germany; and
Division of Clinical Pharmacology, Medizinische Klinik, Klinikum Innenstadt of the Ludwig-Maximilians-University Munich, München, Germany
| Abstract |
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or ß)
up-regulated production of IL-3, IL-5, IL-6, and IL-9 as well as TNF,
i.e., cytokines implicated in many inflammatory processes including
those associated with allergies and helminthic infections. IL-1 did not
induce significant cytokine release in the absence of ionomycin or
IgE/Ag, suggesting that Ca-dependent signaling was required.
IL-1-mediated enhancement of cytokine expression was confirmed at the
mRNA level by Northern blot and/or RT-PCR analysis. Our study reveals a
role for IL-1 in the up-regulation of multiple mast cell-derived
cytokines. Moreover, we identify mast cells as a novel source of IL-9.
These results are of particular importance in the light of recent
reports that strongly support a central role of IL-9 in allergic lung
inflammation and in host defense against worm
infections. | Introduction |
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Upon IgE receptor-mediated or Ca-ionophore-induced activation, primary
mouse bone marrow-derived mast cells
(BMMC)2 and permanent
mast cell lines can produce a panel of different cytokines including
IL-3, -4, -5, -6, and -13 as well as GM-CSF and TNF
(6, 7, 8, 9, 10). Similarly, also human mast cells have been
identified as a source of multiple cytokines in vitro as well as in
clinically relevant situations in vivo, e.g., in allergic inflammations
(reviewed in Refs. 11, 12, 13). In these previous studies, the
profile of mast cell cytokine secretion displayed a striking overlap
with the cytokine pattern produced by a subset of T helper lymphocytes
called Th2 (14). Activated Th2 cells are known to mediate
humoral immune responses and produce IL-4, IL-5, IL-6, IL-10, and IL-13
(15, 16), while activated Th1 cells and their prototypic
cytokine products IL-2 and IFN-
are involved in cell-mediated immune
reactions including delayed-type hypersensitivity responses
(17).
Murine IL-9, a multifunctional T cell-derived cytokine
(18) previously called P40 (19, 20), T cell
growth factor III (21), or mast cell
growth-enhancing activity (22, 23, 24, 25) has been detected in
the supernatants of Th2 but not Th1 clones (26). In the
murine system, IL-1 has been identified as an essential
costimulatory signal for IL-9 production by activated cultures of
established Th2 cells (27). IL-9 production in vitro by
murine naive CD4+ T cells was clearly IL-2
dependent, synergistically enhanced by a combination of TGF-ß and
IL-4, and inhibited by IFN-
(28). A similar IL-2
dependence of IL-9 expression was found in human naive
CD4+ T cells, which produced augmented levels of
IL-9 through the autocrine actions of IL-4 and IL-10 (29).
Recently, a role of IL-9 as a candidate gene for asthma
(30, 31, 32) has been further strongly supported by
experimental results with IL-9 transgenic mice challenged with
allergens in vivo (33, 34).
In this paper, we demonstrate that the proinflammatory mediator IL-1 (35) up-regulates the expression of several cytokine mRNAs and thus promotes enhanced production of the corresponding Th2-related cytokine proteins including IL-9 in primary murine BMMC activated by ionomycin or IgE/Ag. Hence, our study reveals a broad regulatory role for IL-1 in mast cell cytokine expression and we newly identify primary activated mast cells as a source of IL-9. Our results emphasize a potential clinical importance of IL-1 and mast cells in the amplification of Th2-type immune responses during parasitic or retroviral infections (36, 37, 38), in Th2-dependent inflammatory skin reactions (39, 40, 41), and in allergic diseases (42).
| Materials and Methods |
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BALB/c mice were bred in our animal facilities under specific pathogen-free conditions until the age of 6 wk and then kept under conventional conditions (GSF, Munich, Germany). Mice of both sexes were used as bone marrow donors at ages of 828 wk.
Cytokines and Abs
Recombinant murine (mu) kit-ligand (KL) was expressed in
Escherichia coli and purified by affinity chromatography as
described by Reisbach et al. (43). The following cytokines
were commercially obtained as listed: rmuIL-1ß, rmuTNF, and rat
anti-mouse IL-4R mAb (code 1688-01; Genzyme, Boston, MA), rmuIL-3
(Bachem Biochemica, Heidelberg, Germany), recombinant human (hu) IL-6
(Life Technologies, Grand Island, NY), rhuIL-1 receptor antagonist
(IL-1Ra), and rmuIL-9 (British Biotechnology, Oxon, U.K.). RmuIL-4 was
provided by Dr. W. Müller (Institut für Genetik,
Universität Köln, Köln, Germany). RhuIL-1
was a
kind gift from Dr. R. Munker (Med. Klinik III,
Universitätsklinikum Grosshadern, München, Germany) and
originated from Hoffmann-La Roche (Basel, Switzerland). RhuIL-1ß
(commercial product from Genzyme) was provided by Dr. J. Bujia (Klinik
und Poliklinik für Hals-, Nasen- und Ohrenkranke,
Universitätsklinikum Grosshadern, München, Germany). The
neutralizing rat anti-muIL-3 Ab 19B3.1 (44) was a kind
gift of Dr. J. Abrams (DNAX, Palo Alto, CA). The rat anti-muIL-6 Ab
6B4 (45) was provided by Dr. J. Van Snick (Ludwig
Institute for Cancer Research, Brussels, Belgium). As a source of
rmuIL-3 or rmuIL-5, we used batches of supernatants derived from
X63Ag8-653 myeloma cells transfected with a retroviral vector carrying
the mouse IL-3 or IL-5 genes (46). These transfected cell
lines were kindly provided by Dr. F. Melchers (Basel Institute for
Immunology, Basel, Switzerland). Hybridoma cells secreting
DNP33-BSA-specific IgE Ab were originally developed at the Weizmann
Institute of Science (Rehovot, Israel) (47) and kindly
provided by Dr. B. Reck (Max Planck Institut für Immunbiologie,
Freiburg, Germany). Anti-DNP-BSA IgE was purified by separation on a
protein G column.
Mast cell cultures
BALB/c bone marrow cells were suspended at 5 x
104/ml in RPMI 1640 medium including 20% FCS, 2
mM L-glutamine, 100 U/ml penicillin-streptomycin,
10-5 M
-thioglycerol, and 1% rmuIL-3
(pretested supernatant from IL-3 gene-transfected X63Ag8-653 cells
(46) containing about 1000 U/ml IL-3) and then distributed
into 96-well microplates (Nunc, Wiesbaden, Germany) (200 µl/well) and
incubated at 37°C in a fully humidified atmosphere (10%
CO2 in air). After 14 days, all nonadherent cells
from two 96-well plates were pooled and transferred to culture flasks
containing fresh culture medium (50 ml/flask). Following another 2 wk
in culture, we regularly obtained suspensions of apparently homogeneous
populations of BMMC (97100% Alcian
blue+/Safranin-) as
described previously (48).
Cytokine induction experiments
If not otherwise indicated, primary BMMC (in vitro age, 4 wk)
were grown in the presence of IL-3. BMMC were washed twice, suspended
at 1 x 106 cells/ml in RPMI 1640 medium including 1
U/ml rmuIL-3 (a dose warranting cellular survival) and the other
supplements described above, and then transferred into 24-well plates
(Nunc) (0.5 ml/well) containing the Ca-ionophore ionomycin (Sigma, St.
Louis, MO) and/or the potentially activating cytokines to be tested in
5- or 10-µl volumes (replicate wells/group). Ionomycin and various
cytokines were tested at the following range of concentrations (given
in parentheses): ionomycin (0.254.0 µM), rhuIL-1
(0.110 U/ml),
rhuIL-1ß, rmuIL-1ß, and rhuIL-6 (0.110.0 ng/ml, respectively),
rmuTNF-
(0.220.0 ng/ml). In experiments with rhuIL-1Ra (20 ng/ml
finally) or anti-IL-4R mAb (20 µg/ml finally), the mast cells had
been preincubated (2 h; 37°C) with these agents before the addition
of IL-1 and ionomycin. To study the effects of IL-1 in mast cells
activated via cross-linking of their high-affinity Fc
RI, 24-well
plates were coated with 10 µg DNP-BSA/0.5 ml PBS/well and incubated
overnight at 4°C. The coated wells were washed twice with PBS (1
ml/well). Mast cells (10 x 106/ml) were
preincubated in a shaking water bath (1h; 37°C) with
anti-DNP-BSA-specific IgE (10 µg/ml finally, diluted in Tyrodes
buffer containing 0.05 g/100 ml gelatin). Then the cells were washed
twice in PBS and suspended at 1 x 106/ml in
RPMI 1640 medium including the supplements described above but lacking
IL-3. The cell suspension was plated (0.5 ml/well, 2 wells/group) in
the absence or presence of IL-1 into Ag-coated wells and incubated at
37°C (10% CO2 in air). Cell-free supernatants
were usually harvested after 24 or 48 h and stored at -20°C
until assayed.
Cell lines and cytokine bio-assays
The biological activities of several murine cytokines were quantitated using specific indicator cell lines and pure recombinant reference cytokines in short-term proliferation assays (MTT test (49) or measurement of [3H]thymidine uptake) defining 1 U/ml as a cytokine concentration provoking a half-maximum response in the respective assay (for details see the references cited). The following cell lines have been employed: 32Dcl.23 for IL-3 (22), 7TD1 for IL-6 (45), and TS1.C3 (19) or ST2/K9.4a2 (26) for IL-9 measurements. A standard cytotoxicity assay for TNF bioactivity using a TNF-sensitive L929 fibroblast cell line was used as described (50). The specificities of the biological assays were confirmed employing neutralizing doses of specific anti-mouse cytokine mAb. At the relevant concentrations, the agents and cytokines tested in the cytokine induction assays did not interfere with cytokine activities in the different biological assays.
Murine cytokine-specific ELISA tests
The two-site ELISA tests employed in the present study have been described recently as described in the references cited below. The following anti-mouse cytokine Abs have been used: affinity-purified anti-mouse IL-4 mAb 11B11, rabbit anti-mouse IL-4 antiserum, as well as biotinylated swine anti-rabbit antiserum (Dakopatts, Hamburg, Germany) (51), affinity purified anti-muIL-5 mAb TRFK5 and biotinylated anti-muIL-5 mAb TRFK4 (26), hamster anti-muIL-9 mAb C12 (gift of Dr. J. Van Snick, Ludwig Institute, Brussels, Belgium), and biotinylated rat anti-muIL-9 mAb 229.4 (28).
Northern blot analysis
Total cellular RNA was prepared from BMMC by the single step acid guanidinium thiocyanate-phenol-chloroform extraction method (52). RNA was glyoxylated and electrophoresed through a 1.0% agarose gel and blotted by vacuum blotting onto nylon membranes (Hybond-N; Amersham, Braunschweig, Germany). Hybridization and stringency washes of blots were performed as previously described (53). The probe used for hybridization was a cDNA fragment of murine IL-9 (20) (0.36-kb NcoI-BamHI fragment; kindly provided by Dr. J. Van Snick), which had been labeled with [32P]dCTP by the random priming method (Megaprime DNA labeling system; Amersham). Transfer efficiency was controlled by an additional hybridization to a murine 28SrRNA probe, kindly provided by Dr. I. Grummt (German Cancer Research Center, Heidelberg, Germany). Autoradiographic analysis was performed with the Fuji digital imaging system (exposition on Fuji imaging plates and subsequent evaluation with a Fujix BAS1000 Bio-Imaging Analyzer; Fuji, Düsseldorf, Germany). The amounts of IL-9 mRNA were normalized based on 28S rRNA levels.
RT-PCR analysis
The primer pairs and the method used to detect transcripts for the housekeeping gene GAPDH and for specific mouse cytokine genes (IL-3, IL-6, IL-9) have been described previously (54, 55).
| Results |
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Because mast cells are regarded as important cellular regulators
and effectors of many immunological and inflammatory reactions, which
also involve the action of various proinflammatory mediators (e.g.,
IL-1, IL-6, TNF), we were interested in potential influences of these
mediators on mast cell cytokine production. BMMC generated in the
presence of IL-3 were activated following a standard protocol
(ionomycin (1 µM), 24 h) in the absence or presence of rhu
IL-1
(2 U/ml). Mast cell supernatants were then tested for a panel
of different cytokines (i.e., IL-3, IL-4, IL-5, IL-6, IL-9, and TNF)
employing specific ELISAs or biological assays. As exemplified for
IL-3, IL-6, IL-9, and TNF in Fig. 1
,
there was no substantial constitutive cytokine production and only
moderate cytokine production after activation with ionomycin alone.
However, when in addition to the Ca-ionophore also rhuIL-1
(2 U/ml)
was provided during the induction period, substantially higher
concentrations of IL-3, IL-6, IL-9, and TNF were measured in 24-h
supernatants (Fig. 1
). In contrast, no significant differences were
found between ionomycin-induced IL-4 levels of mast cell supernatants
in the presence or absence of rhuIL-1
as a coactivating agent (data
not shown). In the absence of the Ca-ionophore, IL-1 induced only small
amounts of IL-6 but no other cytokines (Fig. 1
), indicating that
Ca-dependent signaling was required for cytokine induction by IL-1.
This IL-1 effect was dose dependent, as illustrated for IL-3, IL-5,
IL-6, and IL-9 induction with a maximum at 110 U/ml IL-1
(Fig. 2
), and highly specific, as preincubation
(1 h) of BMMC with 20 ng/ml rhuIL-1Ra abolished the action of a
saturating dose of rhuIL-1
(2.5 U/ml), an effect that could be
efficiently counteracted by increasing the IL-1 dose (demonstrated for
IL-9 production in Fig. 3
). A similar
enhancement of cytokine production in ionomycin-activated BMMC was
noted with rhuIL-1ß or rmuIL-1ß (saturating maximum effects at
1.010 ng/ml) but not with rhuIL-6 (0.110.0 ng/ml) or rmuTNF
(0.220.0 ng/ml) (data not shown).
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When ionomycin/IL-1-activated BMMC were followed over an induction
period of 672 h, a remarkable difference in the kinetics of IL-9
production was observed compared with all other cytokines analyzed. As
shown for IL-3, IL-5, and IL-6, these bio-activities increased almost
constantly over time without a significant time delay after activation,
whereas IL-9 production was clearly delayed with a very moderate
increase from 6 to 24 h and a dramatic increase from 24 to 48
h (Fig. 5
).
|
Fig. 6
shows a typical result of a
Northern blot analysis of IL-9 expression in mast cells activated for
12, 24, or 48 h with either ionomycin alone or with ionomycin plus
IL-1. In mast cells activated by ionomycin alone, IL-9 mRNA expression
could not be detected before 48 h. In contrast, after activation
with ionomycin plus IL-1, a faint IL-9-specific signal was already
observed after 12 h and strong additional increases of IL-9 mRNA
expression were seen after 24 and 48 h (Fig. 6
). An IL-1-mediated
enhanced expression of IL-9- as well as IL-3- and IL-6-specific mRNAs
was also observed by RT-PCR analysis of activated BMMC (data not
shown).
|
The delayed kinetics of IL-9 mRNA expression (Fig. 6
) and IL-9
protein secretion (Fig. 5
) in mast cells activated by ionomycin plus
IL-1 and the known enhancing effects of IL-4 on IL-9 production by
activated murine and human T cells (28, 29) prompted us to
investigate a possible autocrine role of IL-4 in IL-9 production by
mast cells. As shown in Fig. 7
,
significantly reduced IL-9 levels were measured 48 h after
activation of BMMC with ionomycin/IL-1 when the cells were treated with
an Ab blocking the mouse IL-4 receptor (anti-IL-4R mAb). In
contrast, the decline of the IL-4 levels observed in the absence of
anti-IL-4R mAb from 24 to 48 h after mast cell activation
could be completely prevented in its presence, indicating that
substantial amounts of endogenously produced IL-4 were consumed by the
mast cells 24 to 48 h after activation (Fig. 7
). Moreover, this
anti-IL-4R mAb also reduced the levels of IL-3 and IL-6, revealing
the autocrine potential of endogeneous IL-4 to further enhance the
production of these cytokines in activated mast cells (Fig. 7
).
|
It is generally accepted that BMMC produced and maintained in
vitro in the presence of IL-3 represent a population of relatively
immature c-kit-expressing mast cells with the potential to
further differentiate either along the mucosal or the connective
tissue-type mast cell lineage both in vitro and in vivo
(1). Therefore, we tested the cytokine-producing capacity
of BMMC cultured for 2 wk with IL-3 and then switched for another 2 wk
to different cytokine conditions (IL-3 or IL-3/IL-4 or IL-3/IL-4/KL).
Compared with BMMC grown in IL-3 alone, BMMC generated in the
additional presence of IL-4 or IL-4 plus KL are known to contain
significantly higher concentrations of histamine (56, 57),
and a substantial proportion of them stained positively with Safranine
(Table I
), indicating the presence of
phenotypically more mature cells with some characteristics of
connective tissue-type or serosal mast cells. Compared with activated
BMMC grown in IL-3 alone, those BMMC grown with IL-3/IL-4 and more
pronounced with IL-3/IL-4/KL displayed a strikingly increased capacity
to secrete IL-3, IL-6, and IL-9 in response to ionomycin/IL-1, roughly
correlating with the grade of Safranine positivity of the
different mast cell populations tested
(BMMCIL-3/IL-4/KL >
BMMCIL-3/IL-4 > BMMCIL-3)
(Fig. 8
and Table I
). However, rather low
and quite comparable amounts of these cytokines were produced by these
different groups of BMMC populations after activation with ionomycin
alone (Fig. 8
).
|
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We next determined whether IL-1 would be able to augment cytokine
production of mast cells under more physiological conditions in vitro,
i.e., following activation via cross-linking of their high-affinity IgE
receptors (Fc
RI) by IgE/Ag. As shown in Fig. 9
, no IL-9 activities could be measured
in supernatants of IgE/Ag-activated BMMC unless also IL-1
was
present during the induction period of 48 h, although the cytokine
concentrations did not reach the high levels of
ionomycin/IL-1-stimulated BMMC cultures. Similarly, IL-1 was able to
augment IL-3 and IL-6 production in BMMC following cross-linking of
their IgE receptors (data not shown).
|
| Discussion |
|---|
|
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The phylogenetically highly conserved IL-1 system involves the
primarily cell-associated IL-1
, the soluble IL-1ß proteolytically
cleaved from the IL-1 protein precursor by caspase-1, the naturally
occurring IL-1Ra, as well as membrane-associated and soluble forms of
two different IL-1 receptors (IL-1RI and IL-1RII), with IL-1RII
functioning exclusively as a decoy target (35). The IL-1
family of cytokines has profound effects on the pathogenesis of
inflammatory and infectious diseases (35). Most of the
cytokines described in our present paper (i.e., IL-3, IL-5, IL-6, IL-9,
TNF) were reported to be intimately involved in Th2-polarized immune
reactions, e.g., in allergic inflammations (63, 64, 65) and in
host defense reactions against parasites (36, 37, 66).
In contrast, mast cells have long been known to be functionally involved in many inflammatory reactions including allergic inflammation as well as host immune responses to worm parasites (1, 2, 3), while their life-saving role in bacterial infections was discovered only recently (67, 68, 69).
While we (22, 23, 24, 25) and others (70) have previously described effects of IL-9 on the growth and functional activity of murine mast cells in vitro, recent reports on IL-9 transgenic mice confirmed the mastocytosis-inducing activity of this cytokine in vivo (71) and supported the idea that IL-9-driven mast cells can help to resolve experimental helminthic infections (72, 73). Moreover, recently IL-9 was suggested as a candidate gene for asthma (32), a hypothesis additionally strengthened by experimental results with IL-9 transgenic mice challenged with allergens in vivo (33, 34).
We think that IL-1 could provide a powerful coactivating stimulus to mast cells in the course of a variety of inflammatory reactions and infectious diseases, particularly including helminthic infections and allergic inflammations. Mast cells may then augment inflammatory cascades by the enhanced secretion of cytokines (e.g., IL-3, IL-5, IL-6, IL-9, and TNF) with paracrine and even autocrine actions (e.g., IL-3 and IL-9).
Our finding that activated mast cells costimulated with IL-1 are able to secrete high amounts of IL-9 in vitro may have potential clinical implications in the light of recent reports emphasizing important roles of IL-9 both in host defense against worm parasites (72, 73) and in allergic inflammation (32, 33, 34).
| Acknowledgments |
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| Footnotes |
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2 Abbreviations used in this paper: BMMC, bone marrow-derived mast cells; KL, kit ligand; mu, murine; hu, human; IL-1Ra, IL-1 receptor antagonist. ![]()
Received for publication October 4, 1999. Accepted for publication March 14, 2000.
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