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*
Departments of Immunology and Bacteriology, Western Infirmary, and
Centre for Rheumatic Diseases, Royal Infirmary, University of Glasgow, Glasgow, United Kingdom; and
Department of Pharmacology, School of Medicine Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil
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and 
)
commensurate with the capacity to rapidly respond to IL-18. IL-18
induced cytokine and chemokine release from neutrophils that was
protein synthesis dependent, up-regulated CD11b expression, induced
granule release, and enhanced the respiratory burst following exposure
to fMLP, but had no effect upon the rate of neutrophil apoptosis. The
capacity to release cytokine and chemokine was significantly enhanced
in neutrophils derived from rheumatoid arthritis synovial fluid,
indicating differential responsiveness to IL-18 dependent upon prior
neutrophil activation in vivo. Finally, IL-18 administration promoted
neutrophil accumulation in vivo, whereas IL-18 neutralization
suppressed the severity of footpad inflammation following carrageenan
injection. The latter was accompanied by reduction in tissue
myeloperoxidase expression and suppressed local TNF- production.
Together, these data define a novel role for IL-18 in activating
neutrophils and thereby promoting early innate immune
responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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expression, and
IFN-
, TNF-, and GM-CSF production by Th1 clones (3).
However, at early stages of T cell differentiation, IL-18 can promote
either Th1 or Th2 responses independently of IL-4 or IL-12, suggesting
a broader role in functional T cell differentiation than that
originally recognized (4). IL-18 enhances T cell and NK
cell cytotoxicity and directly induces IFN- production by NK cells,
suggesting some role in innate responses (5). IL-18 can
also directly induce monokine production by macrophages that
constitutively express IL-18R (6). Commensurate with a
putative early role in immune responses, IL-18 mRNA is widely
distributed, facilitating rapid generation of cytokine if required.
Synthesis of IL-18 protein has been described thus far in macrophages,
Kupffer cells, keratinocytes, fibroblasts, chondrocytes, and
osteoblasts (6, 7, 8, 9, 10, 11). IL-18 is functionally regulated by
IL-18 binding protein, a recently described Ig-like cytokine receptor
that strongly suppresses developing Th1 responses through IL-18
neutralization (12). IL-18 exerts important effects during host responses to infection. Thus, protective Th1 responses during murine Cryptococcus neoformans or Yersinia infections may be abrogated or enhanced by manipulation of IL-18 expression (13, 14), clearly indicating a role in microbial host defense. IL-18-deficient mice exhibit altered responsiveness to Mycobacterium bovis, Propionibacterium acnes, and Leishmania major, associated with suppressed T cell/NK cell activation (5, 15). Moreover, we recently demonstrated that IL-18-deficient mice exhibit reduced capacity to kill Staphylococcus aureus in vivo associated with increased severity of septic arthritis (15). The precise mechanisms mediating the latter are currently unclear but could reflect impaired neutrophil function. Compatible with this, neutralization of IL-18 before LPS challenge reduces tissue myeloperoxidase (MPO)4 levels, suggesting that IL-18 is implicated at some stage in neutrophil activation (16). However, thus far, the direct effects of IL-18 on neutrophil function have not been defined.
Recent data indicate a role for IL-18 in the pathogenesis of several
inflammatory disease states. IL-18 mRNA is up-regulated in nonobese
diabetic mice and the murine IL-18 gene maps to the idd2
susceptibility locus (17). Similarly, IL-18 deficiency is
associated with altered myeloid oligodendrocyte glycoprotein
peptide-specific autoreactive T cell responses and amelioration of
autoimmune encephalomyelitis (18). In humans, IL-18
expression has been reported in psoriasis, inflammatory bowel disease,
and sarcoidosis (19, 20, 21). We recently demonstrated that
IL-18 is present in significant levels in the rheumatoid arthritis (RA)
synovium (6), where it induces and sustains articular Th1
cell responses and independently promotes TNF- production.
IL-18-deficient mice develop significantly reduced incidence and
severity of collagen-induced arthritis compared with wild-type mice,
associated with suppressed TNF- production and Th1 immune responses
ex vivo (22). Finally, Ab-mediated IL-18 neutralization
suppresses streptococcal cell wall-induced arthritis through an
IFN--independent mechanism (23). These data indicate
that IL-18 is of importance during developing and sustained
inflammatory pathologic states.
In the present study, we have explored the hypothesis that the functional role of IL-18 in innate immune responses may extend to neutrophil activation, and that this property of IL-18 may be of importance in chronic inflammatory diseases. Neutrophil infiltration is a feature of many autoimmune lesions including psoriasis, inflammatory bowel disease, and RA, although their qualitative and quantitative contribution therein is unclear. In RA, neutrophils constitute up to 90% of synovial fluid (SF) cells and are present also at the cartilage-pannus junction. Activated neutrophils secrete many of those cytokines and extracellular matrix-degradative enzymes implicated in RA pathogenesis (reviewed in Refs. 24 and 25). Circulating neutrophils in RA patients exhibit several features indicative of partial activation (24, 26). The present report documents for the first time direct biologic effects of IL-18 upon neutrophils. IL-18 enhanced adhesion molecule expression, respiratory burst, and chemokine production by peripheral blood (PB) neutrophils through constitutive IL-18R expression. Because prior in vivo priming could alter subsequent neutrophil function, we extended our studies to include neutrophils derived from RA synovium, which demonstrates that IL-18 induces high levels of proinflammatory cytokine production and degranulation by tissue neutrophils.
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Materials and Methods |
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PB from normal donors (n = 11) or RA PB (n = 11) and SF (n = 14) samples were collected from patients who satisfied the American College of Rheumatology 1987 criteria (27). Neutrophils were isolated as previously described (28) and resuspended in complete RPMI 1640 medium supplemented with 2 mM L-glutamine, 100 IU penicillin, and 100 µg/ml streptomycin (all obtained from Life Technologies, Paisley, U.K.). The purity of the isolated neutrophils was assessed by FACS analysis and found to be 95% pure with <1% CD14, <2% CD19, and <2% CD3 cells.
RT-PCR and quantification of mRNA
The presence of IL-18R on neutrophils at the mRNA level was
investigated by RT-PCR. RNA was extracted from purified neutrophils
using RNAzol B (Biogenesis, Poole, U.K.), and cDNA was generated by
reverse transcription using the SuperScript II system (Life
Technologies) according to the manufacturer’s recommendations.
PCR analysis of the cDNA was conducted using the
recommended reaction mix (Life Technologies) with the following
primers: IL-18R, 5'-ACTTGTCATTAGGTTGGCGG-3' and
5'-ACTCAGTCACCCACTGGTCC-3'; -actin,
5'-AGGGCAGTGATCTCCTTCTGCATCCT-3' and
5'-CCACACTGTGCCCATCTACGAGGGGT-3' (Sigma-Genosys, Pampisford, U.K.)
Reaction conditions were as follows: denaturing at 94°C
for 40 s followed by 35 cycles of denaturing at 94°C for 40
s, annealing at 56°C for 30 s, and extending at 72°C for
60 s. The 305-bp product was confirmed by cloning into TA vector
(Invitrogen, Groningen, The Netherlands) and sequencing with T7 DNase
polymerase kit (Amersham, Little Chalfont, U.K.) according to the
manufacturer’s protocol. Finally, cDNA levels of murine TNF-
and hypoxanthine phosphoribosyltransferase were quantitated by
real-time PCR using an ABI prism 7700 sequence detector according to
the manufacturer’s instructions (PerkinElmer Applied Biosystems,
Foster City, CA). Amplification was achieved using an initial cycle of
50°C for 2 min and 95°C for 10 min followed by 40 cycles of 95°C
for 15 s and 50°C for 1 min. The cDNA levels during the linear
phase of amplification were normalized against hypoxanthine
phosphoribosyltransferase controls. Calculations were made in
triplicate and expressed as mean ± SD.
Neutrophil cytokine production in response to IL-18
Neutrophils were placed in 96-well flat-bottom plates (Nunc, Roskilde, Denmark) at 2 x 106 cells/ml in complete RPMI 1640 medium supplemented with 10% FCS (Life Technologies) and stimulated with recombinant human (rh)IL-18 (6) at 1, 10, or 100 ng/ml for 24 h at 37°C. To determine whether de novo protein synthesis is induced by IL-18 activation, cyclohexamide or actinomycin D (both at 2 µg/ml, obtained from Sigma-Aldrich, Poole, U.K.) was added to cells for 30 min before IL-18 addition. Finally, dexamethasone and methotrexate (both at 1 µM, obtained from Sigma) were used in inhibition studies. Culture supernatants were stored at -20°C until estimated by ELISA.
ELISA
IL-1 and IL-8 were detected using paired Abs (R&D Systems,
Oxon, U.K.), and TNF- was also detected using paired Abs (BD
PharMingen, San Diego, CA). Recombinant IL-1 and IL-8 were obtained
from R&D Systems, and TNF- was a gift from Dr. G. R. Adolf
(Boehringer Ingelheim Research and Development, Vienna,
Austria). The detection limit for TNF- and IL-1 was <10
pg/ml, IL-8 was <20 pg/ml. Lactoferrin was detected as previously
described (29).
FACS analysis
To assess the purity of PB and SF neutrophils, cells were labeled with Abs against CD3, CD14, CD15, and CD19 (all obtained from Sigma) according to the manufacturer’s recommendations. Neutrophil IL-18R expression was determined by FACS analysis with monoclonal anti-IL-18R (R&D Systems) as previously described (6). Neutrophil activation was assessed by CD11b expression. Briefly, heparinized venous blood was diluted 1/10 in IMDM supplement with 2 mM L-glutamine, 100 IU penicillin, and 100 µg/ml streptomycin (all obtained from Life Technologies). Cells were cultured for 1 h at 37°C either in the presence or absence of 100 ng/ml rhIL-18 and then labeled with anti-CD11b (Sigma). Propidium iodide (Sigma) and annexin V (BD PharMingen) staining for apoptosis was conducted according to the respective manufacturer’s recommendations, and cells were observed for signs of apoptosis up to 24 h cultured either in medium alone or with 100 ng/ml rhIL-18. All stained cells were analyzed using a BD Biosciences (San Jose, CA) FACSCalibur with CellQuest software.
Effect of IL-18 on neutrophil respiratory burst
Mediators such as GM-CSF and TNF- have been shown to have
"priming" effects on neutrophils, altering the subsequent
respiratory burst in response to stimuli such as immune complexes, PMA,
or the bacterial chemoattractant fMLP. Neutrophils were placed in
24-well flat-bottom plates (Nunc) at 107 cells/ml
in medium with 10% FCS and stimulated with 100 ng/ml rhIL-18 for
1 h at 37°C. Neutrophils were transferred to triplicate wells of
a luminometer microtiter plate in the presence of 10 µM luminol
solution (Sigma). A total of 1 µM fMLP (Sigma) was added, and the
plate wasread immediately in a MLX microtiter plate luminometer (Dynex,
Middlesex, U.K.).
In vivo estimation of IL-18 function
Carrageenan-induced inflammation was initiated in BALB/c mice as described previously (30). Neutralizing monoclonal anti-IL-18 Ab or control Ab (both at 25 µg/animal, obtained from R&D Systems) was administered i.p. 30 min before and 24 h after carrageenan injection into the right hind footpad. The change in footpad thickness between the right and left hind limbs was measured with a dial caliper (Kroeplin, Munich, Germany). In some experiments, 4- to 5-wk-old male BALB/c mice received i.p. injection (0.5 ml total volume) of recombinant murine IL-18 (R&D Systems) at doses indicated or of PBS, and neutrophil accumulation within the peritoneal cavity was calculated at various times thereafter as previously described (31). Briefly, after IL-18 or PBS injection, the animals were killed and the peritoneal cavity cells were harvested by washing the cavity with 5 ml PBS containing 1 mM EDTA. The volume recovered was similar in all groups tested. Total counts were performed in a cell counter (Coulter Counter CBC5; Coulter, Miami, FL) and differential cell counts enumerated on cytocentrifuge (Shandon, Pittsburgh, PA) slides stained with Rosenfeld. The differential count (200 cells) was performed under a light microscope and the results presented as number of neutrophils per cavity.
MPO assay
Footpads were removed 24 h after carrageenan challenge, and the content of MPO was determined as described previously (16). MPO activity per gram of footpad was calculated such that 1 U MPO equals the amount of enzyme that will reduce 1 µM peroxide/min. MPO activity (U/g) = (A460)(13.5)/weight (g). A460 is the change in absorbance of 460 nm light from 1–3 min after initiation of the reaction.
Statistical analysis
Statistical analysis was performed using Minitab software (Minitab, State College, PA). Significant differences were determined using the Mann-Whitney U test or Student’s t test as indicated.
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We first sought evidence of IL-18R expression. Neutrophils derived
from both normal donors and RA patients constitutively expressed IL-18R
- and IL-18R -chain mRNA (Fig. 1
A). Surface expression of
IL-18R was confirmed by FACS in PB samples from both normal donors
and RA patients. No significant difference in the level of expression
was observed in PB derived from RA or normal donors (Fig. 1B). Similar data were obtained using a whole-blood culture
FACS method, indicating that such expression was unlikely to reflect
partial activation during purification (data not shown). These data
suggest that IL-18 could initiate early biologic effects on
neutrophils. To determine whether IL-18R expression is sustained
after tissue entry, we examined IL-18R expression by FACS in
neutrophils derived from RA SF. Significantly higher levels of
IL-18R were observed, indicating that IL-18 responsiveness could be
maintained, or even enhanced, within a chronic inflammatory lesion.
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Constitutive expression of IL-18R indicated that IL-18 could
exert early effects on neutrophil adhesion. The i.p. injection of
recombinant murine IL-18 into BALB/c mice induced rapid influx of
neutrophils that was maximal at 4 h and reduced by 48 h (Fig. 2, A and B).
Similar data were obtained when IL-18 was injected in an identical
protocol into C3H/HEJ mice, indicating that low-level LPS contamination
is unlikely to explain our observations (data not shown). To
investigate potential mechanisms underlying this observation, we
examined up-regulation of CD11b. PB neutrophils from RA patients
expressed significantly higher basal levels of CD11b than normal
donors, indicating partial prior activation in vivo. Incubation of PB
neutrophils from either normal donors or RA patients with rhIL-18
resulted in a significant increase in CD11b expression compared with
control cells (Table I). Maximal CD11b
expression was similar in RA and normal donor groups.
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Neutrophils are abundant in inflammatory lesions, and their
ability to produce inflammatory mediators has recently been recognized.
PB neutrophils produced high levels of IL-8 in a dose-dependant manner
in response to IL-18, providing a further mechanism whereby IL-18 may
promote neutrophil recruitment into inflammatory lesions (Fig. 3A). Of interest, IL-8
production to IL-18 was reduced in RA donors. This may reflect
concomitant drug therapy, because preincubation with either
dexamethasone or methotrexate ablated IL-18-mediated cytokine release
(Fig. 3B). Low levels of IL-1 production were observed
from PB neutrophils derived from normal donors only (Fig. 3C). Finally, a minority of patient and normal PB donor
neutrophils produced low levels of TNF- (data not shown). In
contrast, SF neutrophils released high levels of IL-8, IL-1, and
TNF- in response to IL-18 in a dose-dependent manner (Fig. 3, A, C, and D). Thus, the potential for
ex vivo cytokine release appeared to be qualitatively and
quantitatively altered by prior in vivo activation. To determine
whether de novo protein synthesis was required for cytokine production,
neutrophils were cultured in the presence of actinomycin D and
cyclohexamide, leading to highly significant suppression of all
cytokine production (Fig. 4, A–D). Thus, de novo cytokine synthesis, rather than granule
release, most likely explains our observations.
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The presence of a neutrophil granule constituent,
lactoferrin, in culture supernatants may serve as a surrogate marker
for neutrophil degranulation (24). Lactoferrin release
increased dose dependently in response to IL-18 (Fig. 5). Furthermore, lactoferrin release in
response to IL-18 (100 ng/ml) was significantly higher from SF
neutrophils than from RA or normal PB neutrophils, commensurate with in
situ activation in the synovial compartment.
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Prior incubation of neutrophils with IL-18 led to significant
enhancement of the response to fMLP (p < 0.05)
that was evident in normal and in RA-derived PB neutrophils (Fig. 6). However, SF neutrophils failed to
respond to fMLP following preincubation with IL-18. This is consistent
with the previously described phenomenon of neutrophil "exhaustion"
with respect to respiratory burst (32).
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Antiapoptotic effects of innate cytokines including IL-15 and GM-CSF have been previously observed for neutrophils (33, 34). Therefore, we investigated whether IL-18 can promote neutrophil survival at sites of inflammation. After up to 24 h of incubation with IL-18 (100 ng/ml), apoptosis was determined by propidium iodide and annexin V staining. No difference was observed in IL-18-treated cells compared with medium controls at any time point (data not shown).
Anti-IL-18 Ab suppresses neutrophil-mediated inflammation in vivo
Finally, we investigated whether in vivo neutralization of IL-18
could modify neutrophil-mediated acute inflammatory responses.
Anti-IL-18 Ab was administered to BALB/c mice before footpad
carrageenan challenge. Anti-IL-18 recipient mice exhibited
significantly reduced paw pad edema compared with control mice
(p < 0.01; Fig. 7A). Consistent with this,
tissue MPO activity was significantly reduced in anti-IL-18-treated
mice (Fig. 7B). Cytokine mRNA expression assessed by
real-time PCR demonstrated significant suppression of footpad TNF-
expression (Fig. 7C). Importantly, lymph node cytokine mRNA
(by TaqMan PCR) and cellular proliferation and cytokine production
(IFN-, TNF-, and IL-6) to anti-CD3 in draining lymph node
cultures was unaltered in anti-IL-18-treated mice (data not shown),
suggesting that the primary effects of Ab administration were manifest
locally.
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Discussion |
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Several recent data indicate an important role for IL-18 in host
defense to a broad range of microbes, including C. neoformans, Y.
enterocoliticus, M. bovis, P. acnes, L. major, and S.
aureus (5, 13, 14). IL-18-mediated protective effects
have been proposed to operate mainly through regulation of T cell and
NK cell activation and enhanced monokine production (5, 35). Our data indicate that polymorphonuclear cell activation
will also be of importance, especially during Gram-positive bacterial
infection, in which neutrophil function is paramount. We demonstrated
constitutive IL-18R -chain expression, indicating that
IL-18-dependent responses may be rapidly recruited. Several reports
indicate that IL-18 is present at an early stage following S.
aureus infection (36, 37). Addition of IL-18 binding
protein in vitro promptly down-regulates IFN- production following
S. epidermidis infection in whole-blood cultures
(38). We have also observed that intracellular IL-18
protein expression is detectable within 15 min of S. aureus
(Cowan strain) ingestion by human monocytes (data not shown). Our data
suggest that, following microbial challenge, IL-18 can rapidly enhance
neutrophil recruitment and killing activity. Commensurate with this,
IL-18-deficient mice exhibit reduced killing of S. aureus in
vivo (15), suggesting that the IL-18-dependent pathways
elucidated here may be of critical importance.
Higher levels of IL-18R expression were detected in neutrophils derived
from RA SF than from blood. Wide variability was observed in the
magnitude of neutrophil IL-18R expression between individuals and in
cells from different tissue compartments. Because samples were
collected and treated in a similar manner, it is unlikely that
processing artifact can explain all of the observed variation. Given
its relative importance in regulating acquired and innate responses, it
is likely that IL-18R -chain expression will be tightly regulated.
Whereas IL-18R expression on T cells is regulated in part by IL-12, the
factors that alter IL-18R expression on neutrophils are unknown and are
being sought in our laboratory. IL-18R is a member of the Toll/IL-1R
family, suggesting that the IL-18/IL-18R system has evolved as a
component of the innate response (39). Pathways that
modulate IL-18R will likely modulate potential neutrophil function
and may in due course have implications for Toll/IL-1R family
regulation on neutrophils and other cell types.
Sustained IL-18 expression has been reported in a number of chronic inflammatory disease states including RA, inflammatory bowel disease, and sarcoidosis (6, 20, 21). The mechanisms whereby IL-18 could contribute to disease pathogenesis remain poorly defined. An important component of the present study was to determine whether effects of IL-18 on neutrophils could extend beyond acute inflammation (e.g., carrageenan induced) to include some contribution to chronic synovitis. In RA, proposed mechanisms whereby IL-18 can drive synovitis include regulation of local Th1 responses, direct effects on proinflammatory monokine production, enhanced NO production, and direct effects on chondrocytes and matrix degradation (6, 11). Commensurate with high levels of IL-18R expression, synovial neutrophils retained a high degree of responsiveness to IL-18, leading to significant cytokine and chemokine production. The quantitative contribution of neutrophils to cytokine expression in RA is unclear but could be considerable given their abundance within the synovial compartment. That IL-18 also induced degranulation is of importance because granule contents of synovial neutrophils include collagenase, cathepsin G, gelatinase, elastase, and phospholipase A2 (24, 25), all of which may be of functional significance in promoting articular destruction. Although neutrophils are detected in low numbers at the cartilage-pannus junction (25, 40), the majority are trafficked to SF. Thus, IL-18-activated neutrophils could contribute directly to altered cartilage turnover, because SF directly bathes the cartilage matrix, or could modulate synovial lining layer cells through adjacent release of cytokines or chemokines (25).
It is of interest that recent effective therapeutic developments in RA,
namely TNF- blockade and leflunamide, exhibit powerful effects on
neutrophil recruitment in vivo (41, 42). RA PB neutrophils
expressed higher basal levels of CD11b yet produced significantly less
IL-8 in response to IL-18 than normal PB. We also observed suppression
of the IL-18 response in vitro by corticosteroid and to a lesser extent
by methotrexate. In contrast, the effects of IL-18 on respiratory burst
and granule release were similar on RA and normal PB neutrophils. This
suggests complex regulation of discrete neutrophil functions, amenable
to distinct interventions. PB neutrophils from RA patients exhibit
evidence of prior activation compared with normal PB controls that
could further explain variable responses to IL-18 observed in this
study.
Taken together, our data suggest a role for IL-18 in innate neutrophil lead responses in addition to its clearly defined role in T cell maturation. Our data have two-edged consequences for therapeutic targeting of IL-18. IL-18 blockade may abrogate host toxic effects of neutrophils but could simultaneously potentiate infections in which neutrophils are essential in host responses.
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Acknowledgments |
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Footnotes |
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2 B.P.L. and S.C. contributed equally to this paper.
3 Address correspondence and reprint requests to Dr. Iain. B. McInnes, Center for Rheumatic Diseases, Glasgow Royal Infirmary, University of Glasgow, 10 Alexandra Parade, Glasgow, U.K. E-mail address: i.b.mcinnes{at}clinmed.gla.ac.uk
4 Abbreviations used in this paper used in this paper: MPO, myeloperoxidase; RA, rheumatoid arthritis; PB, peripheral blood; SF, synovial fluid; rh, recombinant human.
Received for publication March 12, 2001. Accepted for publication June 27, 2001.
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