ARTICLE
INTRODUCTION
Interleukin-1 (IL-1) is a pleiotropic inflammatory cytokine which plays
a central role in immunity and inflammation. The spectrum of action of
IL-1 encompasses activity on cells of hematopoietic origin, from immature
precursors to mature leukocytes, as well as on components of the vessel
wall and cells of mesenchymal and epithelial origin [1, 2]. In addition
to a direct effect on target cells, the induction of secondary cytokines,
including IL-6, colony-stimulating factors and chemokines (e.g. MCP-1
and IL-8), is involved in many of the in vitro and in vivo
activities of IL-1.
Two receptors for IL-1, type I (IL-1RI) and type II (IL-1RII), have
been identified and cloned [3-5]. IL-1Rs are usually co-expressed in various
cell types at different levels, with IL-1RII being the predominant form
present on phagocytic cells [2-6]. Recently, an accessory protein which
associates with and increases the binding affinity of IL-1RI has been
described [7]. IL-1 signaling activity appears to be mediated exclusively
via the IL-1RI [8-10], whereas the IL-1RII has no signaling property
and acts in myelomonocytic cells as a "decoy" for IL-1, which prevents
IL-1 from binding to IL-1RI [2, 11].
IL-1 not only induces the secretion of secondary cytokines, such as
chemokines, but can also act in synergy with them to amplify their responses
on target cells. It has been recently reported that exposure of human
neutrophils (PMN) to IL-1 induces the potentiation of PMN response to
IL-8 and other stimuli, evaluated in terms of granule enzyme release,
calcium transients, phospholipase D (PLD) activity and superoxide release
[12, 13]. The IL-1ß effect was receptor mediated since it was completely
blocked by the IL-1 receptor antagonist (IL-1ra).
The present study was undertaken to address two main questions. Firstly,
which of the two IL-1R is involved in IL-1ß priming effect. Secondly,
to investigate whether IL-1ß could potentiate chemotactic response,
the eponimous function of chemokines. The latter question is motivated
by the fact that no studies are available on IL-1R involvement in effects
that require a short (< 10 min) exposure to IL-1.
The data here reported show that IL-1ß can strongly synergize
with suboptimal or even inactive IL-8 concentrations in inducing PMN chemotaxis.
In addition, by the use of specific blocking antibodies, we show that
IL-1RI is the only receptor responsible for the fast priming activity
of IL-1ß.
MATERIALS AND METHODS
Reagents and chemicals
Cytochalasin B (CB) was from Sigma Chemical Co. (St. Louis, MO). PBS
was from Gibco Labs. (Grand Island, NY). Hanks' balanced salt solution
(HBSS) was from Irvine Scientific (Santa Ana, CA). Silica gel 60 plates
were from Merck (Darmstadt, Germany). Isolymph and dextran T500 were from
Gallard-Schlesinger Chemical Manufacturing Corp. (Carle Place, NY). 1,2-Diacyl-PA
was from Serdary Res. Labs. (London, Ontario, Canada). 1-O-[3H]octadecyl-sn-glycero-3-phosphocholine
(122 Ci/mmol) was from Amersham (Amersham, U.K.). Diff-Quik was from Harleco
(Gibbstown, NJ). IL-8 was purchased from PeproTech (Rocky Hill, NJ). M1
(blocking mAb anti-IL-1RI) and M22 (blocking mAb anti-IL-1RII) were kindly
provided by Dr J. E. Sims (Immunex Corp., Seattle, WA). IL-1ß (human
mature polypeptide 117-269, expressed in E. coli and purified to
>= 99%, specific activity 3 x 107 IU/mg) and IL-1ra (human
recombinant mature polypeptide 26-152, expressed in E. coli and
purified to >= 99%) were from Dompé S.p.A. and were endotoxin-free
(< = 0.1 EU/mg by LAL assay).
Isolation of PMN
Human PMN were prepared to > 95% purity from heparinized venous blood
collected from healthy donors by dextran sedimentation followed by centrifugation
over isolymph and hypotonic lysis of contaminating red blood cells [14].
PMN viability was > 95% in all experiments, as measured by Trypan blue
dye exclusion.
Migration assay
Migration of PMN was evaluated using a microchamber technique in a 48
well microchemotaxis chamber (Neuro Probe Inc., Cabin John, MD), as described
elsewhere [15]. Twenty-five microliters of medium (HBSS with 0.2% BSA)
or IL-8 were seeded in the lower compartment of the chemotaxis chamber.
Fifty microliters of cell suspension (1.5 x 106/ml) preincubated
at 37° C for 10 min in the presence or absence of different concentrations
of IL-1ß were seeded in the upper compartment. The time of 10 min
was chosen from time-course experiments, as the shortest time sufficient
to obtain a consistent effect. IL-1ß can be either washed off after
priming or left in the assay without any variation of results. In some
experiments, blocking monoclonal antibodies M1 and M22 (10 µg/ml)
were incubated with the cells for 10 min before the addition of IL-1ß.
The two compartments of the chemotactic chamber were separated by a 5-µm
PVP-free polycarbonate filter (Nucleopore Co., Pleasanton, CA).
The chambers were incubated at 37° C in air with 5% CO2
for 30 min. At the end of incubation, filters were removed, fixed, stained
with Diff-Quik and five oil immersion fields were counted after sample
coding.
Measurement of elastase
release
Isolated human PMN were resuspended (107/ml) in PBS containing
0.1% BSA and preincubated with 10 5 M CB at 37°
C for 10 min. IL-1ß was added at the concentrations and the time
indicated. After preincubation, 200 µl aliquots of cells were stimulated
with 200 µl of IL-8 appropriately diluted in PBS/0.1% BSA, supplemented
with CaCl2 and MgCl2 to yield a final concentration
of 0.9 mM and 0.5 mM, respectively. After 30 min, the samples were centrifuged
and supernatants analyzed for elastase activity. Elastase enzymatic activity
in PMN supernatants was measured at 410 nm as hydrolysis of MeO-succinyl-Ala-Ala-Pro-Val-p-nitroanilide
(Calbiochem, San Diego, CA; 600 µM final concentration). Results
are expressed as variations of optical density per minute ( O.D.
x 103/min) recorded in the first 10 min of the assay. During
this time enzymatic kinetics are linear [16].
Measurement of phospholipase D (PLD) activity.
Isolated PMN were resuspended (3.5 x 107/ml) in HBSS and incubated
with 2 µCi/ml 1-O-[3H]octadecyl-sn-glycero-3-phosphocholine
at 37° C for 30 min, as previously described [17, 18]. 1-O-[3H]alkyl-2-acyl-sn-glycero-3-phosphocholine-labeled
PMN (107/ml) were prewarmed in the presence of 10
5 M CB at 37° C for 5 min in the presence or absence of M1
or M22 antibodies, exposed to IL-1ß for 30 min and then stimulated
for 1 min with IL-8. Reactions were terminated by withdrawal of 0.5-ml
sample aliquots into 2 ml of chloroform/methanol/formic acid (1:2:0.2,
v/v) and vigorous mixing [17, 18]. Total lipids were extracted by a modification
of the procedure of Bligh and Dyer [19] and lipids were separated on TLC
silica gel 60 plates in a solvent system made up of ethyl acetate/isooctane/glacial
acetic acid/H2O (110:50:20:100, v/v), as described previously
[17, 18]. Separated lipid fractions were identified by comparing their
migration with those of appropriate lipid standards, after staining TLC
plates with CBB R-250 (Bio-Rad, Hercules, CA) or exposing them to I2
vapor. After TLC and scraping of plates, radioactivity present in individual
lipid fractions was determined by liquid scintillation counting and calculated
as a percentage of total counts recovered from the lane.
Statistical analysis
Statistical analysis was performed by one-way analysis of variance ANOVA
followed by Dunnett's test (multiple comparisons) or Student's t-test.
RESULTS
The role of IL-1RI and IL-1RII in IL-1ß priming of PMN stimulated
by IL-8 was investigated. Two, well-characterized blocking antibodies
against IL-1RI (M1) and IL-1RII (M22) were used to discriminate the role
of the two receptors in IL-1ß priming of PMN. As previously reported
[12], preincubation of PMN (10 min) with IL-1ß (100 ng/ml) significantly
increased the release of elastase activity (1.81 ± 0.075 fold) induced
by IL-8 (100 ng/ml). A brief (10 min) pretreatment of PMN with M1 strongly
blocked IL-1ß priming effect (84 ± 4% inhibition; n = 3). In
the same experimental conditions, M22 did not inhibit IL-1ß priming
effect but it could significantly increase elastase release (1.3 ±
0.15 fold; p < 0.05). Comparable results were also obtained preincubating
PMN with IL-1ß for 30 min, previously reported to be the optimal
preincubation time for IL-1ß priming effect (data not shown; 12).
The two antibodies alone did not change basal release of elastase (Figure
1). IL-1ß (100 ng/ml) by itself did not alter basal cell
elastase release (data not shown).
Priming of elastase release by IL-1ß was found to be associated
with an increase of PLD activity in IL-8-stimulated cells [12]. Therefore,
it was of interest to investigate the effect of M1 and M22 antibodies
on IL-8-stimulated PLD activity in IL-1ß-primed PMN. Results in
Figure 2 show that preincubation
of PMN with IL-1ß results in an increase of 1-O-[3H]
alkyl-2-acyl-phosphatidic acid ([3H]-EAPA) formation, compared
to cells stimulated with IL-8 alone. The priming effect of IL-1ß
was strongly inhibited by M1 antibody (75% inhibition of the IL-1ß
effect over IL-8). In the same experimental conditions, addition of M22
to IL-1ß-primed PMN resulted in an amplification of PLD activity
(23% of increase versus IL-1ß primed group), similar to that
observed in the experiments concerning elastase release.
To evaluate whether IL-1ß could exert a priming activity on multiple
IL-8-mediated biological activities, its effect on IL-8-induced PMN chemotaxis
was investigated. The chemotactic effect of IL-8 is dose-dependent starting
from 1.5 ng/ml and reaching a peak at 25 ng/ml (not shown). As shown in
Figure 3A, preincubation
of PMN with IL-1ß (10 min; 100 ng/ml) significantly increased IL-8-induced
chemotaxis. The effect of IL-1ß was present at suboptimal concentrations
of IL-8 (0.75-3 ng/ml), whereas it was not measurable at higher IL-8 concentrations
(>= 6 ng/ml). IL-1ß (100 ng/ml) by itself did not alter basal
cell migration (Figure 3A)
and its priming effect was not increased by more prolonged preincubation
(data not shown). The priming action of IL-1ß was concentration-dependent
starting at 10 ng/ml and reaching maximal levels of stimulation at 100
ng/ml (Figure 3B). Priming
by IL-1ß was completely blocked in the presence of IL-1ra (100 µg/ml)
or M1 (10 µg/ml). These results indicate that in the chemotactic
response also the effect of IL-1ß is specific and mediated by IL-1RI.
IL-1ra or M1 alone did not exhibit chemotactic or chemokinetic activity
(data not shown).
DISCUSSION
PMN play a key role in the defence against invasion by bacteria, parasites,
viruses and non-self cells. Chemotactic signals generated at the site
of inflammation in response to proinflammatory cytokines (e.g. IL-1) are
responsible for the recruitment of leukocytes from the blood compartment
into injured tissues [20-22]. Proinflammatory cytokines may also act in
concert with chemotactic factors in the activation of leukocyte inflammatory
potential [23-25].
In this study, we report that a brief exposure to IL-1ß induces
a potentiation of both PMN elastase release and chemotactic response to
IL-8, the prototype of C-X-C chemokines. The effect of IL-1ß was
rapid, being already observed 10 min after stimulation, and concentration
dependent starting at 10 ng/ml and reaching maximal levels of stimulation
at 100 ng/ml both regarding elastase release and in chemotaxis assay (Figures
1 and 3; ref. 12). IL-1ß alone did not induce elastase release
nor did it promote PMN chemotaxis over the concentration range tested
(1-100 ng/ml). For elastase release, the priming effect of IL-1ß
was present over a wide range of IL-8 concentrations (10-1000 ng/ml; 12).
On the other hand, priming of chemotaxis was observed only at suboptimal
(3-6 ng/ml) or inactive (e.g. 0.75 ng/ml) IL-8 concentrations (Figure
3A). This might be explained by considering that the primary activity
of IL-8 on PMN is chemotaxis, which is maximal at 5-10 ng/ml, making impossible
any amplifying effect by IL-1ß unless IL-8 is present at suboptimal
concentrations. On the other hand, the effect of IL-8 on PMN secondary
granule release is much less evident and still does not reach maximal
levels at 1 µg/ml [12], thus making possible a further amplification
of the effect by IL-1ß even at high IL-8 doses.
It has long been known that the predominant IL-1-binding molecule present
on the surface of PMN is the IL-1RII [6]. Recent work has clearly established
that IL-1 activity is mediated exclusively via IL-1RI in many different
cell types including T and pre-B cells, hepatic cells, osteoblasts, monocytes
and PMN [8, 10, 11, 26]. Available data are consistent with a model in
which IL-1RII competes with IL-1RI for IL-1 binding, thus acting as a
decoy for IL-1 and inhibiting its activity [2]. Consistent with this hypothesis,
several molecules with anti-inflammatory properties (IL-4, IL-13 and dexamethasone)
augment the surface expression and the release of IL-1RII on PMN and human
mononuclear phagocytes [11, 27, 28]. However, no data are available on
the relative role of IL-1RII on short (min) effects of IL-1 such as priming
to IL-8 responsiveness [12].
The priming effect of IL-1ß on both elastase release and chemotaxis
of PMN could be completely blocked by the action of IL-1ra, indicating
a receptor mediated mechanism (Figure
3B and ref. 12). In addition, in the presence of M1, a specific
blocking antibody to IL-1RI, the priming effect on IL-1ß on both
elastase release and chemotaxis was completely prevented (Figures
1 and 3). Conversely, M22, a blocking antibody against IL-1RII,
was inactive or increased the priming effect of IL-1ß (Figure
1). These results are consistent with the model of IL-1RI being
the only signaling receptor. Overexpression of IL-1RII in keratinocytes
and fibroblasts was associated with an impairment of IL-1 response caused
by the withdrawal of IL-1 molecules by their binding to IL-1RI [29, 30].
These data can explain the increased response to IL-1ß observed
in the presence of M22 mAb in the present study. In fact, the anti-IL-1RII
antibody could increase elastase release in IL-1ß-primed PMN by
inhibiting the decoy receptor and allowing better IL-1ß efficacy.
The main role of IL-1RI in the priming action of IL-1ß was also
suggested by the use of SMIL-3, an IL-1ß mutein in which the QGEESNDKIP
sequence (in position 164-173) was substituted with the corresponding
sequence of IL-1ra [31]. This mutein shows impaired binding to IL-1RI,
and thus an higher affinity for the decoy IL-1RII than for IL-1RI. When
used in priming assays of elastase release, the priming effect of SMIL-3
was about ten fold less than that of IL-1ß, thus indicating that
in fact the priming effect should be principally mediated through IL-1RI
(data not shown).
Priming of elastase release by IL-1ß was associated with a priming
effect on PLD activity, completely blocked in the presence of M1 antibody
(Figure 1), and with the
influx of calcium across plasma membrane channels [12]. To evaluate the
role of these two second messengers in the chemotactic response of PMN
to IL-8, experiments in the presence of ethanol, to inhibit PA production
[17], or La3+, to block calcium influx [12], were performed.
Similarly to what has been observed for elastase release, the increased
levels of PA production and calcium influx did not appear to play a relevant
role in IL-1ß priming of chemotaxis to IL-8 (data not shown). The
exact mechanism of the priming effect of IL-1ß is under investigation.
In preliminary experiments we have observed that IL-1ß does not
prime PMN stimulated by GROgamma and NAP-2 (S. Sozzani; unpublished).
These two proteins belong to the C-X-C chemokine family like IL-8 but
they bind with high affinity only to one of the two IL-8 receptors, the
C-X-CR2. To better understand the signaling properties of the two IL-8
receptors, we are at present investigating the ability of IL-1ß
to prime other IL-8 biological responses in PMN, including the respiratory
burst and NADPH oxidase activation.
Chemokines are a large superfamily of chemotactic proteins that have
been implicated in several pathological situations, including inflammation,
allergy and immune reactions [32]. IL-1ß is a strong inducer of
chemokines in several cell types. However, the interplay between the IL-1
system and chemokines is much more complex and involves multiple interactions.
IL-1 can also promote the activation of target cells by chemotactic mediators,
as reported in this study, and prolong PMN survival in tissues by preventing
cellular apoptosis [11]. All these actions are pro-inflammatory functions
of IL-1. On the other hand, chemotactic agonists induce the rapid release
(min) of the decoy IL-1RII from the cell surface [33]. The shed receptor
could capture and prevent IL-1 from binding to IL-1RI thus keeping the
inflammatory reaction under control. The relationship between the IL-1
system and chemotactic mediators is quite complex and the fine regulation
of this interaction plays a crucial role in the onset, persistence and
resolution of the inflammatory response.
CONCLUSION
Acknowledgment.
This work was supported by the contract ''Programma Nazionale di Ricerca
sui Sistemi Neurologici Tecnologie della Traduzione del Segnale,
tema 6 Caratterizzazione Genetico-Molecolare della Modulazione della Risposta
Immunitaria con particolare riguardo all'Interazione con il SNC'', granted
to the Consorzio NIRECO by the Italian Ministry of University and Scientific
& Technological Research.
We thank Dr John E. Sims for providing M1 and M22 antibodies; Dr Paolo
Ruggiero for providing IL-1ß and IL-1ra; Dr Gabriella Melillo for
graphic support and Dr Alberto Mantovani for discussion and criticism
of the manuscript.
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