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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4828-4835
Interleukin-15 (IL-15) Induces NF- B Activation and IL-8
Production in Human Neutrophils
By
Patrick P. McDonald,
Maria Pia Russo,
Silvano Ferrini, and
Marco
A. Cassatella
From the Department of General Pathology, University of Verona,
Verona, Italy; and the Centro di Biotecnologie Avanzate, Istituto
Nazionale per la Ricerca sul Cancro, Genova, Italy.
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ABSTRACT |
Interleukin-2 (IL-2) and IL-15 exert similar biological actions,
which largely reflect the fact that their receptors share common  and  subunits; in contrast, distinct  subunits are required for
high-affinity binding of either cytokine to a heterotrimeric receptor
complex. Human neutrophils are known to express both the and subunits of the IL-2/IL-15 receptor complex, and we now report that
they also constitutively express messenger RNA transcripts encoding the
IL-15 receptor chain, suggesting that they possess functional,
heterotrimeric IL-15 receptors. Accordingly, we show that in
neutrophils, IL-15 elicits several functional responses. In particular,
neutrophils synthesize and release IL-8 in response to IL-15, but not
to IL-2. Moreover, a nuclear factor- B (NF-B) DNA-binding activity
was enhanced in nuclear extracts of IL-15-treated neutrophils, which
could be supershifted by antibodies to p50 or RelA. Again, no
detectable effect of IL-2 was observed on this response. In peripheral
blood lymphocytes (PBL), however, both IL-2 and IL-15 were potent
inducers of NF-B activation. Conversely, neither IL-15 nor IL-2
elicited the formation of activator protein-1 (AP-1) DNA-binding
complexes in neutrophils, even though both cytokines were found to
activate these DNA-binding activities in PBL. Collectively, these
observations establish neutrophils as a useful cellular model to
discriminate between the actions of IL-15 and IL-2. More importantly,
this is the first demonstration that IL-15 has the ability to induce
NF-B and AP-1 activation, which further emphasizes the potential
relevance of this newly discovered cytokine to immune and inflammatory
processes.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
INTERLEUKIN-15 (IL-15) IS A recently
discovered cytokine whose known biological actions are strikingly
similar to those of IL-2.1-4 A likely explanation for this
apparent redundancy is that the receptors for both cytokines share
common and subunits (IL-2R and IL-2R, respectively),
which mediate intracellular signaling, and which together form an
intermediate affinity receptor complex.1,2,5-7 In contrast,
high-affinity binding of either IL-15 or IL-2 to a heterotrimeric
receptor complex is mediated by distinct chains. Whereas IL-2R
is specific for IL-2,2,5 a structurally related protein
(termed IL-15R) was recently cloned that specifically binds
IL-15.8
IL-15 has been shown to act on various cells of the immune system,
including T lymphocytes, B lymphocytes, natural killer (NK)
cells,1-4 and more recently, peripheral blood neutrophils (PBN).9 In the latter instance, IL-15 was observed to
induce cytoskeletal rearrangements, to enhance phagocytosis, to
increase the synthesis of several cellular proteins, and to delay
apoptosis.9 Under identical conditions, however, IL-2
failed to affect any of these responses in neutrophils.9
Although these different effects of IL-15 and IL-2 stand in apparent
contrast with observations made in other cell types, they nonetheless
correlate well with the fact that individual IL-2R subunits are
selectively expressed in neutrophils. In this regard, studies from
various laboratories have established that human neutrophils
constitutively express messenger RNA (mRNA) transcripts encoding the
IL-2R and IL-2R, as well as the corresponding proteins on their
surface,10-14 but that IL-2R surface expression is
undetectable in these cells.11-14 Conversely, the ability
of IL-15 to directly elicit or to enhance a series of cellular
processes in these cells has led some authors to postulate that
neutrophils must express specific IL-15R components.9
In the current study, we identified one such component as the IL-15R
chain, whose mRNA was detected in resting neutrophils by RT-PCR; we
also confirmed that neutrophils constitutively express mRNA transcripts
encoding IL-2R and IL-2R. Consistent with the presence of a
high-affinity IL-15 receptor complex in neutrophils, we observed that
IL-15 induces the production of IL-8 in these cells. Moreover, we
report for the first time that IL-15 has the ability to activate the
transcription factors, nuclear factor-B (NF-B), and (depending on
the cell type) activator protein-1 (AP-1), a finding that opens new
perspectives as to the potential involvement of IL-15 in inflammatory
and immune processes.
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MATERIALS AND METHODS |
Antibodies and reagents.
Rabbit antisera to human c-Rel (#1136, raised against an internal
sequence downstream from the nuclear localization signal), p65 RelA
(#1207, against the N-terminal region), p50 NFB1 (#1141, against the
N-terminal region), and p52 NFB2 (#1267, against the N-terminal
region) were a generous gift from Dr N.R. Rice (NCI-Frederick Cancer
Research and Development Center, Frederick, MD). The specificity of
these antisera has already been extensively characterized.15,16 Purified antibodies raised against
RelB, and against proteins of the Jun and Fos families, were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). An oligonucleotide containing tandemly repeated NF-B sites identical to those of the
HIV promoter (5 -gatcaGGGACTTTCCgctgGGGACTTTCC-3) was
kindly provided by G. Trinchieri (Wistar Institute, Philadelphia, PA). An oligonucleotide containing a consensus AP-1 sequence
(5-cgcttgaTGAGTCAgccggaa-3) was from Promega
Corporation (Madison, WI, USA). Ficoll-Paque, T4 polynucleotide kinase,
and poly (dI-dC) were from Pharmacia (Uppsala, Sweden);
[-32 P]-ATP was from ICN (Cleveland, OH). RPMI 1640 was from GIBCO/BRL (Gaithersburg, MD), and low-endotoxin FCS (< 6 pg/mL) from Hyclone (Logan, UT). Recombinant human (rh) IL-15 was
purchased from Genzyme (Cambridge, MA) (and kindly provided by Dr R. Zambello, Department of Clinical Medicine, University of Padova,
Italy), and from R&D Systems (Minneapolis, MN); rh IL-2 was obtained
from both Genzyme and R&D Systems. Acetylated bovine serum albumin
(BSA), cycloheximide, diisopropyl fluorophosphate (DFP),
lipopolysaccharide (LPS), and phenylmethanesulphonyl fluoride (PMSF)
were from Sigma-Aldrich (St Louis, MO). Aprotinin,
4-(2-aminomethyl)benzenesulfonyl fluoride (AEBSF), leupeptin, and
pepstatin A were from Boehringer-Mannheim (Mannheim, Germany). All
other reagents were molecular biology grade, and all buffers and
solutions were prepared using pyrogen-free clinical grade water.
Cell isolation and culture.
PBN were isolated from healthy donors under endotoxin-free conditions
by a modification of the method of Boyum,17 as described earlier.18 As determined by Wright staining and nonspecific esterase cytochemistry, the final neutrophil suspensions consistently contained fewer than 0.5% monocytes; neutrophil viability exceeded 98% after up to 3 hours in culture, as determined by trypan blue exclusion. Peripheral blood mononuclear cells (PBMC) were plated in
uncoated plastic culture wells for 2 hours to promote the adherence of
monocytes; nonadherent cells were gently washed out, yielding a highly
enriched lymphocyte population, hereafter referred to as peripheral
blood lymphocytes (PBL). Purified cell populations were resuspended in
RPMI 1640 supplemented with 10% low-endotoxin fetal calf serum (FCS),
and allowed to equilibrate for 15 minutes at 37°C, before
stimulation with IL-15, IL-2, or LPS.
Electrophoretic mobility shift assays (EMSA).
Neutrophils or PBL (5 × 106 cells/mL) were incubated
in a water bath (37°C, under agitation) in the presence or absence
of the stimuli for the indicated times. Incubations were stopped by
transferring aliquots of the cell suspensions into precooled tubes
containing equivalent volumes of ice-cold RPMI 1640 supplemented with
DFP (2 mmol/L, final concentration), before centrifugation at
2,000g for 2 minutes at 4°C. Cells were resuspended in
ice-cold relaxation buffer (10 mmol/L piperazine-N,
N-bis-[2-ethanesulfonic acid] [PIPES], pH 7.30, 10 mmol/L NaCl,
3.5 mmol/L MgCl2, 0.5 mmol/L ethyleneglycoltetracetic acid
[EGTA], 0.5 mmol/L EDTA, 1 mmol/L dithiothreitol
[DTT]) supplemented with an antiprotease cocktail (1 mmol/L DFP, 1 mmol/L PMSF, 1 mmol/L AEBSF, and 10 µg/mL each of
aprotinin, leupeptin, and pepstatin A, final concentrations). After a
10-minute incubation on ice, cells were disrupted by nitrogen cavitation, using a modification of a previously published
procedure19 that we described elsewhere.20
Nuclear extracts were subsequently prepared and analyzed in EMSA as
described.20
Reverse transcriptase-polymerase chain reaction (RT-PCR) analyses.
Neutrophils or PBMC (5 × 106 cells/mL) were cultured
in polystyrene flasks at 37°C under a 5% CO2
atmosphere. Total RNA was extracted as described
previously,18 and analyzed by RT-PCR as reported
earlier.21 Amplified PCR products were size-fractioned on
1.5% agarose gels; gels were stained with ethidium bromide and
photographed.
Determination of immunoreactive IL-8.
Neutrophils (106 cells/300 µL) were cultured in 24-well
culture plates at 37°C under a 5% CO2 atmosphere, in
the presence or absence of the stimuli, for the indicated times.
Culture supernatants were collected, centrifuged (2,000g, 5 minutes, 4°C) to remove intact cells, snap-frozen in liquid
nitrogen, and stored at  70°C. When cell-associated IL-8 was
measured, 0.5 mL of ice-cold phosphate-buffered saline (PBS) was added
to the wells, and neutrophils were gently scraped and combined with the
small cellular pellet resulting from the centrifugation of culture
supernatants. Cells were then centrifuged (2,000g, 5 minutes,
4°C); the resulting pellets were resuspended in 300 µL of cold
lysis buffer (PBS supplemented with 0.5% NP-40, 5 mmol/L EDTA, 1 mmol/L AEBSF, 1 mmol/L PMSF, and 10 µg/mL each of aprotinin,
leupeptin, and pepstatin A), vigorously vortexed for 30 seconds, and
centrifuged (15,000g, 10 minutes, 4°C) to remove insoluble
material. The resulting supernatants were snap-frozen in liquid
nitrogen and stored at 70°C before analysis. The IL-8
concentration of the culture supernatants or of the corresponding cell
lysates was determined using a specific enzyme-linked immunosorbent
assay (ELISA), as previously described.22 The detection
limit for IL-8 using this assay was 20 pg/mL. Alternatively, a
commercial ELISA kit (R&D Systems) was used to measure IL-8 protein.
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RESULTS |
IL-15, but not IL-2, stimulates IL-8 synthesis and release in human
neutrophils.
In a recent report, Girard et al9 convincingly established
that several neutrophil responses are differentially elicited by IL-15
and IL-2. In particular, IL-15, unlike IL-2, was found to enhance the
synthesis of distinct cellular proteins.9 This prompted us
to investigate the effect of IL-15 and IL-2 towards a well
characterized neutrophil function, ie, the ability to generate chemokines such as IL-8.23 Cells were cultured in the
presence or absence of IL-15 or (as a positive control) 1 µg/mL LPS
for varying lengths of time; culture supernatants were collected, and
their IL-8 content was analyzed by ELISA. As shown in
Fig 1A, 20 nmol/L IL-15 (250 ng/mL)
promoted the release of IL-8 from human neutrophils, albeit to a lesser
extent than LPS. This effect of IL-15 was concentration-dependent, a
threshold effect being observed using 8 nmol/L (100 ng/mL) of the
cytokine (Fig 1B). By contrast, IL-2 (up to 5000 U/mL, ie, ~23
nmol/L) invariably failed to exert any significant effect on this
response (P = .13 versus unstimulated cells in 6 independent
experiments), as shown in Fig 1B. To gain further insight into the
mechanisms whereby IL-15 promotes IL-8 release, cells were pretreated
with cycloheximide, before stimulation with IL-15 or IL-2 and
subsequent determination of IL-8 production. Figure 1C shows that IL-15
potently induced the synthesis of IL-8, and that both IL-8 synthesis
and release were inhibited by cycloheximide in IL-15-treated cells,
indicating that de novo protein synthesis is required for this
response. By contrast, IL-2 neither affected the total production, nor
the release of IL-8 in the same experiments (Fig 1C). Finally, it is
worthy of mention that pretreatment of our IL-15 stocks with polymyxin
B failed to prevent the ability of the cytokine to promote IL-8 release
in neutrophils, thereby making it unlikely that endotoxin contamination
might contribute to the activating properties of IL-15 reported above.
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| Fig 1.
Effect of IL-15 and IL-2 towards the production
of IL-8 in human neutrophils. (A) Cells (106/300 µL) were
cultured at 37°C in the presence or absence (-) of 250 ng/mL IL-15
(ie, 20 nmol/L) or 1 µg/mL LPS for the indicated times (in hours).
Culture supernatants were collected, and their IL-8 concentration was
determined using a specific ELISA. Results are expressed as mean ± standard error of mean (s.e.m.) of duplicate determinations for each
experimental condition. Depicted in this panel is a representative
experiment; the ability of 20 nmol/L IL-15 to induce IL-8 release was
observed in seven independent experiments (P = .002 versus
unstimulated cells). (B) Neutrophils (106/300 µL) were
cultured for 9 hours at 37°C in the presence or absence of
increasing concentrations of either IL-15 (closed squares) or IL-2
(open squares). The IL-8 content of the resulting culture supernatants
was then determined by ELISA. Values are the mean ± s.e.m. of
duplicate determinations for each experimental condition. This
experiment is representative of at least three. (C) Neutrophils
(106/300 µL) were cultured for 20 minutes at 37°C in
the presence of 10 µg/mL cycloheximide (CX) or its diluent (DMSO),
before stimulation with 250 ng/mL IL-15 (ie, 20 nmol/L),
103 U/mL IL-2 (~5 nmol/L), or diluent control (ctrl), for
8 hours at 37°C. Cell-free culture supernatants and the
corresponding cell pellets were collected, and their respective IL-8
concentrations were determined by ELISA. Values are the mean ± s.e.m.
of averaged duplicate determinations from three independent
experiments. Open bars, IL-8 release; shaded bars, total IL-8
production (ie, released + cell-associated). *, P < .04 relative to control cells, using Student's t-test for paired
data; CX treatment also yielded significantly lower (P < .05)
values relative to the matched controls for all conditions tested.
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IL-15, but not IL-2, induces NF-B activation in neutrophils.
We recently reported that in neutrophils, many of the stimuli that are
known to induce IL-8 production also have the ability to activate
NF-B.20 We therefore examined whether this transcription factor can be detected in nuclear extracts from neutrophils stimulated with either IL-15 or IL-2. As a positive control, neutrophils were also
stimulated with LPS, which is a powerful NF-B activator in these
cells.20 As shown in Fig 2A,
exposure of neutrophils to 20 nmol/L IL-15 (250 ng/mL) resulted in the
enhanced detection of a nuclear NF-B DNA-binding activity, which
comigrated with the LPS-inducible NF-B complex previously
characterized as containing primarily p50 and RelA.20 This
effect of IL-15 was rapid and transient, because binding of the
IL-15-inducible complex to the NF-B probe was already detectable
within 5 minutes, was still elevated at 30 minutes, and had returned to
basal levels by 60 minutes. Dose-response experiments additionally
showed that a threshold concentration of 8 nmol/L IL-15 (100 ng/mL) is
required to detect an effect towards NF-B activation (data not
shown). By contrast, three different commercial IL-2 preparations
consistently failed to induce any NF-B DNA-binding activity in human
neutrophils, using up to 103 U/mL (ie, ~5 nmol/L) IL-2
(Fig 2A and data not shown). The general lack of effect of IL-2 towards
neutrophils could not be attributed to a poor biological activity of
our IL-2 preparations, because in the same experiments, IL-2 strongly
activated NF-B in autologous PBL (Fig 2A), as expected. Importantly,
IL-15 was also found to induce NF-B activation in human PBL (Fig
2A), thereby showing that this IL-15-elicited response is not
restricted to neutrophils. It must be noted that the relative ability
of IL-15 and IL-2 to activate NF-B in PBL showed some variation
between donors, with IL-15 being somewhat more potent in three out of
five experiments (Fig 2A), whereas IL-2 was the more potent stimulus in
the remainder. Finally, supershift experiments performed using either
neutrophil or PBL nuclear extracts showed that in both cell types, the
IL-15-inducible NF-B complex probably consists of p50-RelA (Fig
2B).
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| Fig 2.
Effect of IL-15 and IL-2 towards the activation of
nuclear NF-B DNA-binding activities in human polymorphonuclear
neutrophils (PMN) and PBL. (A) Neutrophils were cultured for the
indicated times (in minutes), and autologous PBL were cultured for 15 minutes in the presence or absence of 250 ng/mL IL-15 (ie, 20 nmol/L),
103 U/mL IL-2 (~5 nmol/L), or 100 ng/mL LPS. Nuclear
extracts were prepared and analyzed in EMSA using a consensus NF-B
oligonucleotide probe. The amount of extract used in the binding
reactions corresponded to 3.5 µg protein (about 3.1 × 106 cell equivalents) for neutrophils, and to 1.5 µg
protein (about 1.2 × 10 6 cell equivalents) for PBL. This
experiment is representative of six (neutrophils) and five (PBL). (B)
Nuclear extracts from IL-15-activated neutrophils or autologous PBL
were prepared as described in (A), and incubated without antibodies
(-), or with specific antisera to p50, RelA, c-Rel, p52 and RelB,
before the addition of labeled NF-B probe and subsequent EMSA
analysis. The amount of extract used corresponded to 3.5 µg of
protein (neutrophils), and 1.0 µg of protein (PBL). This experiment
is representative of three. Closed arrowheads indicate the inducible
NF-B complex; open arrowheads indicate supershifted bands.
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IL-15 and IL-2 induce AP-1 in lymphocytes, but not in neutrophils.
We also investigated whether IL-15 stimulation of neutrophils might
result in the activation of AP-1, a transcription factor whose
activation often occurs in parallel to that of NF-B in various cell
types. As shown in Fig 3A, neither IL-15
nor IL-2 have the ability to induce AP-1 DNA-binding activity in
neutrophils. This lack of effect was observed regardless of the time
point examined (ranging from 5 minutes to 1 hour; data not shown). By contrast, both cytokines were found to induce an AP-1 doublet in
autologous PBL (Fig 3A, arrowhead); in two out of four experiments, a
faster-migrating doublet was also somewhat enhanced in extracts from
stimulated cells (Fig 3A). The IL-15-inducible complex appeared to
contain c-Fos and JunD, because it was partially supershifted using
antibodies that specifically recognize these proteins, but not by
antibodies to c-Jun, or JunB (Fig 3B); a weak effect of antiFosB
antibodies was also sometimes noted. Identical results were obtained
using nuclear extracts from IL-2-activated PBL (data not shown).
Whereas the above data indicate that complexes containing c-Fos
and/or JunD can be activated by IL-2 and IL-15 in lymphocytes, it cannot be excluded that these complexes contain other proteins as
well. In support of this view, is that the combined use of JunD, c-Fos
and FosB antibodies failed to supershift the inducible AP-1 complexes
to a greater extent than when the same antibodies were used
individually (data not shown).
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| Fig 3.
Effect of IL-15 and IL-2 towards the activation of
nuclear AP-1 DNA-binding activities in human peripheral blood
neutrophils and lymphocytes. (A) Neutrophils or autologous PBL were
cultured for 15 minutes in the presence or absence of 250 ng/mL IL-15
(ie, 20 nmol/L) or 103 U/mL IL-2 (~5 nmol/L); nuclear
extracts were then prepared and analyzed in EMSA using a consensus AP-1
oligonucleotide probe. The amount of extract used in the binding
reactions corresponded to 5 µg protein for neutrophils, and to 2 µg
protein for PBL. This experiment is representative of three
(neutrophils) and four (PBL). (B) Nuclear extracts from
IL-15-activated PBL (1.5 µg of protein) were prepared as described
in (A), and incubated without antibodies (-), or with specific
antibodies to c-jun, junB, junD, c-fos, and fosB, before the addition
of labeled AP-1 probe and subsequent EMSA analysis. This experiment is
representative of three. Closed arrowheads indicate the major inducible
AP-1 complex; open arrowheads indicated supershifted bands.
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Human neutrophils constitutively express the gene encoding
IL-15R.
The various stimulatory effects of IL-15 towards neutrophils suggest
that these cells must express the IL-15R. To clarify this issue,
total RNA was extracted and amplified by RT-PCR, using primers specific
for IL-15R. For comparative purposes, we performed similar analyses
using total RNA extracted from autologous PBMC. As shown in
Fig 4 (lane 1), two amplification products
(at about 530 and 430 base pairs [bp]) were readily detectable in
resting neutrophils and (to a lesser extent) in resting PBMC (lane 2). These two complementary DNA (cDNA) species presumably reflect alternatively spliced IL-15R mRNA isoforms, based on their
respective sizes, and on observations made in other experimental
systems.21,24 Using the same approach, we were also able to
show that neutrophils constitutively express IL-2R and IL-2R mRNA
transcripts (Fig 4, lanes 3 and 5), in agreement with earlier
studies.10-14 We finally performed control experiments to
ensure that the detection of mRNA transcripts encoding the various
IL-15R subunits in our neutrophil preparations did not reflect the
presence of contaminating monocyte or lymphocyte RNA. For this purpose,
we used cDNA primers specific for the IL-6 gene, which is known to be
expressed in peripheral blood monocytes and lymphocytes but not in
neutrophils.18,26,27 As shown in Fig 4 (lane 9), no
amplified RT-PCR product was detectable using these primers in
neutrophils, as opposed to PBMC (lane 10). Similarly, we observed that
although TNF mRNA is induced to similar levels by concanavalin A
(ConA) in both PBMC and autologous neutrophils (as determined in
ribonuclease protection assays), lymphotaxin- mRNA is only detected
in PBMC (our unpublished data). Taken together, the latter observations
make it unlikely that the IL-15R/IL-2R amplification products that we
detected in neutrophils might originate from contaminating lymphocytes
or monocytes. Thus, human neutrophils constitutively express all three
components of the high-affinity IL-15 receptor.
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| Fig 4.
Expression of individual components of the IL-15 receptor
complex in human neutrophils. Total RNA was extracted from resting
neutrophils and autologous PBMC, and processed by RT-PCR using cDNA
primers specific for IL-15R (15R), IL-2R (2R), IL-2R
(2R), -actin, and IL-6. This experiment is representative of
three. Odd-numbered lanes, neutrophils; even-numbered lanes, PBMC; mm,
migration markers (in base pairs [bp]).
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DISCUSSION |
Human neutrophils were recently shown to represent a cellular target
for IL-15.9 In the present study, we extend the current knowledge on IL-15/neutrophil interactions by showing that in these
cells, IL-15 induces the synthesis and release of IL-8, a chemokine
that is thought to play a pivotal role in inflammatory reactions.
Consistent with this finding, Girard et al9 previously showed that in IL-15-treated cells, at least 11 proteins were synthesized de novo. A closer examination of their data further shows
that one of these proteins migrated well below the 14-kD marker, and
had a markedly basic isoelectric point.9 Interestingly, these electrophoretic properties are strikingly similar to those of
IL-8, a protein that has an Mr of about 8 kD in sodium
dodecyl sulfate-polyacrylamide gel electrophoresis
(SDS-PAGE),27 and a pI of 9.4.28 Finally, while
this manuscript was in preparation, Badolato et al29
reported that IL-15 has the ability to induce the production of IL-8 in
human monocytes, in keeping with the current data. Together, these
observations suggest that in an inflammatory setting, the combined
presence of IL-15 and neutrophils (or monocytes) could potentially
result in a significant synthesis of IL-8. That this is indeed the case
in certain pathophysiological conditions grants credibility to this
scenario. For instance, elevated amounts of IL-15 have been detected in
the synovial fluid of arthritic joints,30 which typically
contain large numbers of neutrophils, as well as high concentrations of
IL-8.31 Therefore, through its ability to induce the
synthesis of IL-8, IL-15 could promote the recruitment of additional
neutrophils to inflamed tissues, thereby amplifying ongoing
inflammatory reactions. In addition, IL-15 has the potential to
exacerbate the proinflammatory activities of infiltrating neutrophils
at inflammatory sites, by virtue of its ability to delay neutrophil
apoptosis and to enhance their phagocytic activity (Girard et
al9 and our unpublished data). Collectively, these
considerations suggest a potentially important role for IL-15 in
neutrophil-mediated inflammatory processes.
In contrast to the numerous actions exerted by IL-15, neutrophil
function appears to be only poorly (if at all) affected by IL-2,9,12 and our current observations strongly support
this view. Whereas it has been reported that 103 U/mL IL-2
induces the release of IL-8 in human neutrophils,32 we were
unable to reproduce these observations, even though we used three
commercially available IL-2 preparations, which were all biologically
active, as evidenced by their ability to induce transcription factor
activation in PBL (Fig 3,4). Although we have no explanation for this
discrepancy, it is noteworthy that other investigators have observed
that a broad range of IL-2 concentrations not only failed to elicit
IL-8 release in neutrophils (D. Girard, personal communication), but
also failed to increase the de novo synthesis of any protein in these
cells.9 Similarly, we observed in preliminary studies that
although 25 ng/mL IL-15 (ie, 2 nmol/L) enhanced the phagocytosis of
IgG-opsonized sheep erythrocytes, up to 103 U/mL IL-2 (ie,
~5 nmol/L) was ineffective towards this response (our unpublished
data). This is in good agreement with a recent study, in which similar
concentrations of IL-15 and IL-2 were also found to affect neutrophil
phagocytic activity differentially9; the inability of IL-2
to enhance ongoing phagocytosis had also been reported by other
groups.33-35 Collectively, the different actions of IL-15
and IL-2 correlate well with the fact that individual subunits of the
IL-2/IL-15 receptor complexes are selectively expressed in neutrophils.
Indeed, we show herein that neutrophils constitutively express mRNA
encoding the IL-15R chain; we also confirm earlier reports that had
established that both IL-2R and IL-2R are expressed in resting
neutrophils.10-14 Thus, all three components of the
high-affinity IL-15 receptor are expressed in neutrophils. Conversely,
several groups have reported that IL-2R surface expression is
undetectable in these cells.11-14 The latter observation
might therefore provide a basis for the general lack of effect of IL-2
towards many neutrophil responses, and further indicates that IL-2R
must be a critical component of a fully functional IL-2R complex.
Consistent with this interpretation is that despite the fact that up to
70% of neutrophils express both IL-2R and IL-2R on their
surface, fewer than 20% of the cells actually bind fluorescent-labeled
IL-2.12 Thus, the differential ability of IL-2 and IL-15 to
stimulate human neutrophils might reflect the pattern of expression of
the various IL-2R and IL-15R subunits in this cell type.
In the current study, we also explored one of the potential mechanisms
involved in the stimulatory effect of IL-15 towards IL-8 production in
neutrophils. In this respect, studies performed in other cell types
have established that IL-8 gene expression and release are largely
dependent on NF-B activation.36-38 In keeping with these
observations, we found that IL-15 transiently activates NF-B in
neutrophils. To our knowledge, this represents the first demonstration
that IL-15 is an NF-B inducer in any cell type studied to date.
Conversely, even though the binding of AP-1 complexes to their cognate
sequence within the IL-8 promoter has also been proposed to participate
in transcriptional induction,39,40 this is unlikely to be
the case in IL-15-treated neutrophils because IL-15 did not promote
detectable AP-1 activation in these cells. By comparison, IL-2 failed
to activate either NF-B or AP-1 in neutrophils, consistent with the
observed inability of IL-2 to stimulate IL-8 production in these cells.
In PBL, however, IL-2 proved to be a strong stimulus of NF-B
activation, as expected. More importantly, IL-15 induced NF-B
activation to a comparable extent as did IL-2 in PBL, thereby showing
that this IL-15-elicited response is not restricted to neutrophils. In
addition, both IL-15 and IL-2 were found to induce AP-1 DNA-binding
activities that contain c-Fos and JunD (and perhaps other proteins) in
human PBL. With respect to IL-15, this constitutes the first
demonstration of its ability to induce AP-1 activation, whereas IL-2
had already been reported to activate AP-1 in a gibbon leukemia cell
line41 as well as in the murine CTLL-2 cell
line,42 but surprisingly, not in human cells. Collectively,
these observations suggest that in cells expressing the IL-15R, the
expression of B-dependent genes is likely to be upregulated in
response to IL-15 (as shown herein for the IL-8 gene product in
neutrophils), and that in lymphocytes at least, both IL-15 and IL-2
might likewise induce the expression of genes whose promoters are under
the control of AP-1. In keeping with this view, the IL-2R and TNF
gene promoters contain NF-B sites that are required for
transcriptional inducibility (reviewed in Baeuerle and
Henkel43), and in lymphocytic cells, IL-15 was indeed
reported to induce the accumulation of IL-2R mRNA44 and
to increase TNF production.45 Similarly, the induction of the TNF gene has been reported to involve an AP-1 site in its
promoter,46 which raises the possibility that the induction of TNF production by both IL-15 and IL-2 in human peripheral T
lymphocytes45 might partially reflect the ability of these cytokines to induce AP-1, as observed herein in PBL. Further studies are clearly required to fully document the mechanisms underlying the
actions of IL-15 in various cells of the immune system.
In conclusion, despite the fact that IL-15 and IL-2 exert similar
biological actions in several cell types, neutrophils could represent
an interesting cellular model to discriminate between the effects of
these two cytokines. Conversely, some neutrophil responses were
unaffected by IL-15. In this regard, the inability of IL-15 to induce
AP-1 activation in these cells might provide important insights into
how IL-15 signalling is coupled (or uncoupled) to various aspects of
transcriptional regulation. In a broader context, the envisaged use of
IL-15 in cancer therapy47,48 will have to take into
consideration the potential of IL-15 to induce the expression of
proinflammatory genes through its ability to activate NF-B and AP-1
(as shown herein), as well as distinct members of the signal
transducers and activators of transcription (STAT) family of
transcriptional activators.4
| |
ACKNOWLEDGMENT |
We are indebted to Dr Nancy Rice for having generously provided many
antisera. We also wish to thank Dr Peter Henson for his critical
reading of this manuscript. P.P. McDonald is a Centennial Postdoctoral
Fellow of the Medical Research Council of Canada.
| |
FOOTNOTES |
Submitted May 18, 1998;
accepted August 14, 1998.
Supported by grants from the MURST (fondi 40% e 60%, e
cofinanziamento MURST-Università), the AIRC, and the
Fondazione Cassa di Risparmio VR-VI-BL-AN (progetto Sanità
96/97), as well as from the National Institutes of Health (NIH Grant
No. GM48211).
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Patrick P. McDonald, PhD, National Jewish
Research Center, Neustadt Bldg, Room D501,1400 Jackson St, Denver, CO
80206; e-mail: mcdonaldp{at}njc.org.
| |
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Abstract
Introduction