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Departments of
*
Pathophysiology and Immunology,
Rehabilitation, and
Connective Tissue Disease, Institute of Rheumatology, Warsaw, Poland
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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failed, IL-15 and
IL-2 were equipotent, and PMA + ionomycin was far more efficient in the
induction of IL-17 secretion by PBMCs isolated from healthy blood
donors. Interestingly, synovial fluid cells, in contrast to PBMCs
isolated from patients with rheumatoid arthritis, but not
osteoarthritis, respond to PMA + ionomycin with much lower, comparable
to IL-15-triggered IL-17 secretion. Moreover, PMA + ionomycin-triggered
IL-17 secretion is completely or partially blocked in the presence of
low doses of cyclosporin A or high doses of methylprednisolone,
respectively. IL-15-triggered IL-17 secretion by PBMCs was completely
inhibited by these drugs. Thus, our results suggest for the first time
that IL-15 may represent a physiological trigger that via cyclosporin A
and steroid sensitive pathways leads to the overproduction of IL-17 in
the joints of rheumatoid arthritis patients. |
Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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and IL-1ß that contributes
to the induction of other proinflammatory mediators (IL-6, IL-8,
GM-CSF, and many others), seems to be critical for chronic
inflammation, ultimately resulting in a joint destruction
(1). Recent attempts to neutralize TNF- (using either
neutralizing Abs (2) or soluble receptors
(3)) or IL-1ß (using soluble IL-1R antagonist
(4) yielded promising results in controlling
chronic inflammation and cartilage degradation, respectively. However,
despite these encouraging results, none of these treatments cured the
disease. Therefore, it is likely that cytokines or factors other than
TNF- and IL-1ß also participate in the induction/expansion of
proinflammatory cytokine cascade.
IL-15 was recently identified as one of these candidate mediators. The
concentration of this cytokine is elevated in synovial fluids of RA
patients (5, 6, 7). Interestingly, fibroblast-like
synoviocytes isolated from joints of these patients spontaneously
secrete large amounts of IL-15 that are further elevated on stimulation
with TNF- and IL-1ß (8). After IL-15 activation,
synovial T cells both secrete TNF- directly and induce TNF-
synthesis by macrophages through cognate interactions (7).
In addition, neutralization of IL-15 biological effects using either
soluble IL-15R -chain (9) or antagonist IL-15
mutant/Fc
2a (10) proteins prevents murine
collagen-induced arthritis and delayed type hypersensitivity. Based on
these data, it has been proposed that IL-15 is an important player
leading to/coordinating the induction of proinflammatory cascade
(11, 12).
Recently, the list of potential contributors to the pathogenesis of RA
has been expanded for yet another cytokine, IL-17. This cytokine is
produced by present in RA synovium
CD4+CD45RO+ memory T cells
on activation with PMA/ionomycin or CD3/CD28 Abs (13, 14).
More interesting, IL-17 triggers human synoviocytes to produce IL-6,
IL-8, GM-CSF, and, one of the major mediator of inflammation,
PGE2 (13, 14, 15). The list of
biological effects of IL-17 includes also the stimulation of
granulopoiesis (16), and osteoclastogenesis
(17), the up-regulation of NO synthesis in cultured human
cartilage (18), and triggering of the production of
TNF-, IL-1ß, IL-12, stromelysin, IL-10, and IL-1R antagonist in
human peripheral blood macrophages (19).
In the present report, we hypothesized that elevated in RA, but not in osteoarthritis (OA), synovial IL-15 triggers IL-17 production that, in turn, exerts its biological activity stimulating the production of other proinflammatory mediators. To test this hypothesis we have compared: 1) the levels of IL-17 and IL-15 in serum and synovial fluids of RA and OA patients; and 2) IL-15-triggered in vitro production of IL-17 by PBMCs and synovial fluid mononuclear cells (SFMCs) isolated from these patients. In addition, in attempts to block triggered in vitro IL-17 production, we have applied known immunosuppressive drugs: cyclosporin A (CsA) and methylprednisolone (MP).
We report high (RA) and undetectable (OA) levels of IL-17 that strongly
correlate with the levels of IL-15 in synovial fluids of these
patients. We show for the first time that 1) IL-15, but not TNF-,
stimulates IL-17 production by PBMCs in primary culture and 2) CsA
completely and MP partially block PMA/ionomycin-triggered IL-17
production, whereas IL-15-induced IL-17 production is more sensitive to
MP and slightly less sensitive to CsA. Thus, our data stress the
important role of IL-15 as the inductor of other proinflammatory
cytokines (in our report IL-17). Moreover, it is possible that blockade
of IL-17 production, if occurs in vivo accounts, at least partially,
for good results achieved using CsA in the treatment of RA
(20, 21, 22, 23).
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Recombinant human IL-15, IL-17, and anti-IL-17 IgG1 mAb
(M68) were kindly provided by Dr. T. Troutt (Immunex, Seattle, WA). The
following Abs and cytokines were used: recombinant human TNF-, IL-2,
IL-1ß, IL-6, IL-8, normal mouse IgG1 (mAb), normal goat IgG, protein
G-Sepharose-purified polyclonal goat IgG, anti-TNF-, and
anti-IL-15 from R&D Systems (Minneapolis, MN); polyclonal rabbit
anti-IL-17 from Chemicon (Temecula, CA); polyclonal rabbit
anti-IL-15 from PeproTech (Rocky Hill, NJ); polyclonal rabbit
anti-TNF-, mouse anti-IL-15 mAb (M111), and recombinant
human IL-15 from Genzyme (Cambridge, MA). Peroxidase-conjugated goat
anti-rabbit IgG, o-phenylenediamine, PMA, PHA-P,
ionomycin, and hyaluronidase (type I-S) were obtained from Sigma (St.
Louis, MO). MaxiSorp and 24-well plates were purchased from Nunc
(Roskilde, Denmark). The following immunosuppressive drugs were used in
this study: Solu-Medrol (MP, Upjohn, Paris, France) and Sandimmun
(cyclosporin A, Novartis, Bern, Switzerland).
Patients and control subjects
Paired peripheral blood and synovial fluids were obtained from 15 patients with RA and 8 patients with OA. Blood samples were also obtained from 20 healthy individuals. The patients fulfilled the revised criteria of the American College of Rheumatology for RA (24) or for OA (25). The mean age of RA patients was 51 years (range, 32–76 years), and the mean duration of disease was 75 mo (range, 4–180 mo). The mean ± SD erythrocyte sedimentation rate was 56 ± 39. Nine RA patients were seropositive for IgM rheumatoid factor. Eleven RA patients were receiving prednisolone at low dose, and 4 patients disease-modifying antirheumatic drugs. The mean age of OA patients was 46 years (range, 23–80 years), and the mean duration of disease was 39 mo (range, 3–120 mo). The mean ± SD erythrocyte sedimentation rate was 37 ± 30. All patients with OA received only nonsteroidal antiinflammatory drugs.
Cells and culture conditions
Mononuclear cells were isolated by density gradient
centrifugation of heparinized blood or synovial fluids using Gradisol L
(Biomed, Lublin, Poland). Cells (2 x
106/ml) were cultured in 24-well plates in RPMI
1640 supplemented with 2 mM L-glutamine, 10% FCS (Seromed,
Berlin, Germany), 100 U/ml penicillin, 100 µg/ml streptomycin, and 1
mM HEPES at 37°C in an atmosphere of 95% air and 5%
CO2. Cells were stimulated for 72 h in the
presence or absence of a mixture of PMA (1 nM) and ionomycin (3
µg/ml), or LPS (5 µg/ml, Escherichia coli 055:B5; Difco,
Detroit, MI), or PHA (5 µg/ml), or cytokines: IL-15 (0, 1–300 ng/ml;
Immunex); IL-2 (0, 1–300 ng/ml); TNF- (0, 1–10 ng/ml); IL-6 (10
ng/ml); IL-1ß (10 ng/ml); and IL-8 (10 ng/ml). To study the effect of
neutralizing anti-IL-15 mAb on the IL-15-induced production of
IL-17, the recombinant human IL-15 (100 ng) was incubated with or
without anti-IL-15 mAb (M111, 3 µg) or normal mouse mAb (3 µg)
for 30 min at 37°C before addition to the cell cultures. CsA
(0.005–400 ng/ml) or MP (0.004–20 µg/ml) were added 1 h before
activators. After incubation, the culture supernatants were collected
and clarified by centrifugation at 400 x g for 10 min,
and the concentrations of IL-17 and TNF- were determined by
ELISA.
Immunoassays for IL-17, IL-15, and TNF-
The concentrations of IL-17, IL-15, and TNF- were measured by
a sandwich ELISA using anti-IL-17 mAb (M68), or polyclonal goat IgG
anti-IL-15, or polyclonal goat IgG anti-TNF-, as coating
Abs, respectively. To eliminate interference caused by heterophilic
Abs, the control wells were coated with normal mouse IgG1 (ELISA for
IL-17) or normal goat IgG (ELISA for IL-15) and were applied as a blank
for individual sera and synovial fluids. Next, the polyclonal rabbit
anti-IL-17, anti-IL-15, or anti-TNF- was used as a
detecting Ab, followed by peroxidase-conjugated goat anti-rabbit
IgG. Recombinant human IL-17, IL-15 (Genzyme, Cambridge, MA), and
TNF- were used as standards. The peroxidase reaction was developed
using o-phenylenediamine dihydrochloride as a substrate. The
optical density was measured at 492 nm with an automatic ELISA reader
(LP 400, Diagnostic Pasteur, Marnes la Coquette, France). The detection
limit was 15 pg/ml for IL-17 and IL-15 or 4 pg/ml for TNF-.
Synovial fluids were collected into the tubes with heparin, and the
cells were removed by centrifugation (400 x g, 10
min). Before assay, each synovial fluid was treated with hyaluronidase
at a concentration of 10 U/ml for 80 min at 37°C followed by
centrifugation (12,000 x g, 5 min). This treatment was
performed to reduce the viscosity of synovial fluid. To exclude the
possible interference of rheumatoid factor in the immunoassays, the
sera and synovial fluid were preadsorbed on human -globulin-coated
polystyrene beads (Biomed). Moreover, serum and synovial fluid samples
were diluted twice in PBS containing 0.5% BSA, 0.05% Tween 20, and 1
µg/ml normal mouse IgG1 (ELISA for IL-17) or normal goat IgG (ELISA
for IL-15).
Statistical analysis
Data are expressed as the mean ± SEM. The two-tailed Mann-Whitney U test was used to compare the levels of cytokines in different groups of patients. The paired samples were analyzed by paired two-tailed t test. Correlation between IL-17 and IL-15 levels was assessed with Pearson’s correlation coefficient. Probability values <0.05 were considered statistically significant.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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To measure IL-17 and IL-15 levels, we used highly specific ELISAs
according to protocols described in Patients and Methods. To
eliminate possible interference with rheumatoid factor or heterophilic
Abs, all sera and synovial fluids were: 1) preadsorbed on human
-globulin-coated polystyrene beads; and 2) diluted twice with buffer
containing normal IgG from the same species as coated Abs used in
ELISA. In addition, for each serum and synovial fluid, individual blank
wells were prepared. In these wells, capture anti-IL-17 (or
anti-IL-15) Abs were substituted with preimmune IgG. The OD values
of these wells were considered as the real blank values and therefore
subtracted from the OD values of other wells. We believe that these
precautions prevent the possible interference with rheumatoid factors
in ELISAs for IL-15 and IL-17. Using these pretreatments and ELISAs, we
observed elevated concentrations of IL-17 and IL-15 in synovial fluids
of RA in comparison to OA patients (Fig. 1
). Moreover, we observed strong
correlation between IL-15 and IL-17 levels in the synovial fluids of
these patients (Table I). On the other
hand, there was no correlation between levels of IL-17 in synovial
fluids and serum of the same patients. Finally, we show that elevated
levels of IL-15 were also present in the serum of RA but not OA
patients (Fig. 1). In contrast to IL-17, the levels of IL-15 present in
serum and synovial fluids of the same patients were correlated
(Table I).
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The main cell type producing IL-17 has been identified as a
CD4+CD45RO+ memory T cell
(14). Although cells of this phenotype are abundant in
joints of RA patients (26), the physiological trigger of
IL-17 production and/or its release remains unknown. We hypothesized
that IL-15, also elevated in the joints of RA patients (5, 27) and which may originate from macrophage- and fibroblast-like
synoviocytes (8), participated in the induction of IL-17
production. Indeed, in in vitro experiments, IL-15 in a dose-dependent
manner triggered IL-17 production/secretion by mononuclear cells
isolated from healthy blood donors (Fig. 2). Anti-IL-15 Abs inhibit this effect,
confirming that indeed IL-15 is responsible for the observed rise in
IL-17 production in our culture system (Fig. 3). Among tested stimuli, LPS failed;
IL-15, IL-2, and PHA triggered moderate; and PMA + ionomycin induced
high production of IL-17 (Table II). In
addition, exogenous addition of TNF-, IL-8, or IL-6 also failed to
trigger IL-17 production by PBMCs, whereas IL-1ß was roughly 30%
less potent than IL-15 (Fig. 4). The
mixture of TNF-, IL-6, IL-8 with IL-1ß, or all these cytokines
with IL-15 did not influence the IL-1ß- or IL-15-triggered IL-17
production, respectively (Fig. 4). Interestingly, even after 72 h
of the culture, there was no detectable level of spontaneously released
IL-17. We concluded that IL-15, IL-2, and to a lesser extend IL-1ß
represent physiological factors that trigger IL-17
production/release.
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PBMCs and SFMCs isolated from patients with RA or OA, similar to
PBMCs from healthy blood donors, were also triggered by IL-15 to
produce IL-17 (Fig. 5). However, higher
levels of IL-15-triggered IL-17 secretion (although not statistically
significant) were observed in supernatants of cells isolated from
synovial fluids than from peripheral blood of RA patients (Fig. 5B). Cells isolated from synovial fluid and PB of OA
patients did not differ in their response to IL-15 stimuli (Fig. 5B). Surprisingly, SFMCs from RA, but not from OA, patients
exerted impaired response to PMA + ionomycin-triggered production of
IL-17 (Fig. 5A), whereas PBMCs from the same patients
responded as well as cells isolated from healthy blood donors. Taken
together, these results, showing that synovial fluid cells are
significantly different from PBMCs in their ability to synthesize IL-17
in response to different stimuli, suggest preferential exclusion of
cells capable to respond fully to PMA + ionomycin from RA synovial
fluid. In addition, although not significant in our limited studies,
there is a tendency for positive selection of IL-15-responsive cells
into the synovial fluid.
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Next, we tested the sensitivity of IL-17 production to the known
immunosuppressive drugs CsA and MP. The PMA/ionomycin-triggered IL-17
production by healthy blood donors PBMCs was entirely blocked in the
presence of CsA at concentrations as low as 50 ng/ml (Fig. 6A). Interestingly, the
production of TNF-, measured in the same supernatants, was inhibited
by not more than 80%, even when high concentrations of CsA (400 ng/ml)
were applied (Fig. 6A). In contrast, MP, even at very high
concentrations (20 µg/ml) blocked IL-17 and TNF- production by
only 40 and 60%, respectively (Fig. 6B). In contrast, the
sensitivity of IL-15-triggered IL-17 production to these drugs was
different; lower concentrations of MP and slightly higher of
concentrations of CsA were required for complete inhibition of this
cytokine production (Fig. 7). These
results, showing that like several other cytokines (e.g., IL-2, IL-4)
the production of IL-17 is entirely blocked in the presence of CsA,
suggest that activation of calcineurin and further downstream
dephosphorylation of NF-AT and its translocation to the nucleus play a
pivotal role in the induction of IL-17 transcription.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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). Since submission of the
first version of the paper, the elevation of IL-17 in synovial fluids
of RA and lack of this cytokine in patients with OA have been reported
(17). Based on our current knowledge,
CD4+CD45RO+ memory T cells
are a major T cell subset present in the synovium of RA patients
(26). The same subset of T cells produces large amounts of
IL-17 on stimulation (14). Moreover, in synovial tissue of
RA patients, these cells are immunoreactive with anti-IL-17 Abs
(17). In contrast, a low level of IL-17 has been produced
by CD8+ T cells (13), and
CD8+ cells present in synovial tissue isolated
from RA patients fail to immunoreact with anti-IL-17 Abs
(17). In addition, it has been shown that cultured pieces
of RA synovium (containing
CD4+CD45RO+ cells) also
produce IL-17 (28, 29). Thus, it is very likely that also
in vivo CD4+CD45RO+ T cells
represent the main source of IL-17. There is one report indicating that
only 1% of T cells present in synovial tissue are IL-17 producers.
Further studies are required if the same low proportion of
IL-17-producing cells is preserved in synovial fluid.
Also, we report for the first time that IL-17 production is induced by
IL-15. The significance of this finding is underlined by recent
evidence that IL-15 is one of the most critical factors contributing to
the pathogenesis of RA (11). Indeed, high levels of IL-15
in synovium (5, 27) and according to our finding in serum
of RA but not OA patients (Fig. 1) are present. In addition, IL-15 has
been shown to trigger the production of other proinflammatory cytokines
including TNF- (7, 30), IL-8, monocyte chemotactic
protein 1 (31), IL-12, and IFN- (32). On
the other hand, a recent report indicates that TNF- and IL-1ß may
also stimulate IL-15 production by human synoviocytes (8),
completing the loop of self-perpetuating proinflammatory cytokine
synthesis. Although we fail to detect IL-17 production after addition
of TNF-, IL-6, or IL-8 (Fig. 4), the low level of IL-17 produced in
response to IL-1ß may indicate that the latter cytokine induces
IL-15, which in turn stimulates IL-17 production. Lack of any additive
effect on IL-17 production when both IL-15 and IL-1ß are present in
the culture medium (Fig. 4) supports this notion. Nevertheless, a
direct or indirect effect of IL-1ß, the induction of IL-17 synthesis
in response to IL-15, seems to be a logical consequence of the central
role that the latter cytokine plays in the unbalanced production of
proinflammatory cytokines that accelerate/maintain chronic inflammation
in general, and RA in particular. Known biological properties of IL-17,
as a cytokine inducing other cytokines (33) and a
stimulator of osteoclastogenesis (17), fit very well to
the pattern of cytokines present in RA synovium and changes in bone
resorption (1) and therefore may occur in vivo. Yeh strong
correlation between IL-15 and IL-17 levels in synovial fluids of RA
patients (Table I) supports our hypothesis that IL-15 plays an
important role in the regulation of IL-17 synthesis in vivo. On the
other hand, lack of correlation between levels of IL-17 in synovial
fluids and serum of the same patients (Table I) suggest that IL-17 is
produced mainly, if not exclusively, locally in the synovium of RA
patients. At present, it is not clear why there is no correlation
between levels of IL-15 and IL-17 in the serum of these patients.
One possibility would stress that IL-17-producing
CD4+CD45RO+ cells are
less abundant in the periphery than in the joints of RA patients and
therefore that IL-15 triggers only low levels of IL-17 in the
circulation. The other possibility is that serum contains inhibitor(s)
of biological activity of IL-15. This hypothesis gained recently some
momentum; preliminary results of Gracie et al. (34) show
that, present more frequently in serum than in synovial fluid of RA
patients, soluble IL-15R -chain may block the biological activity of
IL-15. In addition to IL-15, we found that also IL-2 triggers the
production of IL-17 (Table II). However, in contrast to IL-15, IL-2 is
hardly present in the synovium or serum of RA patients
(35). Thus, abundant in RA joints, IL-15, recently shown
also to be produced by fibroblast-like synoviocytes on stimulation with
TNF- and IL-1ß and spontaneously by synovial macrophages
(8), may be responsible for triggering present in affected
joints CD4+CD45RO+ memory T
cells to produce high levels of IL-17. Interestingly, our experiments
show that only IL-1ß, but not TNF-, stimulates IL-17 production.
Although it is not proved yet, we favor the hypothesis that in our
experimental conditions, IL-1 may trigger IL-15 production which in
turn stimulates T-cell to produce IL-17. This hypothesis is supported
by the lack of additive effects of IL-1ß and IL-15 in promoting IL-17
synthesis (Fig. 4). Taken together, the above described scenario adds a
new aspect of the role of CD4+ memory cells in
the pathogenesis of RA (36).
Opposite responses of cells isolated from matched samples of peripheral
blood and synovial fluids from RA patients to IL-15-triggered IL-17
production suggest that 1) IL-17-producing cells isolated from the
synovial fluids of these patients are more sensitive to the IL-15
trigger (e.g., exerting more IL-15 receptors) and that 2) there is a
higher percentage of
CD4+CD45RO+ memory T cells
capable of producing IL-17 in RA synovium than in the peripheral blood.
However, different responses of the same cells stimulated with
PMA/ionomycin, where IL-17 production was significantly higher in
mononuclear cells isolated from peripheral blood (PBMCs) than from
synovial fluid (SFMCs) of RA patients (Fig. 5A), indicate
that although among PBMCs are cells able to produce IL-17 in high
quantities, these cells do not enter the synovium. In addition, it is
possible that IL-15- and PMA + ionomycin- triggered signals that lead
to IL-17 production differ significantly. This hypothesis is supported
by different levels of IL-17 triggered by these stimuli. Experiments
designed to sort out these complexities are currently tested in our
laboratory.
Although, according to our findings, IL-17 lies downstream of IL-15,
controlling the synthesis of IL-17, and therefore inhibiting even
further downstream events of its overproduction, may be of vital
interest of patients with chronic inflammation. This theme led us to
the finding that CsA and, to a lesser extent, MP inhibit PMA +
ionomycin-triggered IL-17 production in vitro (Fig. 6). Both these
drugs completely blocked IL-15-triggered IL-17 production at lower (MP)
and slightly higher (CsA) concentrations (Fig. 7). These differential
effects on the two types of IL-17 induction may be related to the
1000-fold difference in production levels.
CsA exerts its immunosuppressive activity by blocking enzymatic
activity of serine/threonine phosphatase calcineurin that is required
for dephosphorylation of present in the cytosol-phosphorylated
transcription factor NF-AT (37). Failure to
dephosphorylate NF-AT prevents its translocation to the nucleus and
results in lack of the initiation of transcription of several cytokines
(e.g., IL-2, IL-3, IL-4, IFN-) (37). Of four known
isoforms of NF-AT, i.e., NF-AT-p, NF-AT-c, NF-AT-3, and NF-AT-4,
additive or even synergistic effects of NF-AT-p and NF-AT-4 activation
are critical for the development of Th1-type immune response
(38). Because IL-17 is classified as Th1 cytokine
(39), it is likely that NF-AT-p and NF-AT-4 are required
for the induction of its synthesis. However, the experiments testing
this suggestion have to be done.
The use of CsA in RA therapy has been recently investigated, and good results were observed with relatively low doses of this drug (2–5 mg/kg/daily) (20, 21, 22, 23). Consequently, these doses are currently recommended for RA treatment. Low concentrations of CsA that effectively block IL-17 production in vitro are even below the range of concentrations of this drug observed in patients with RA (22, 23). Therefore, it is likely that in in vivo situation, the concentration of CsA, although low, is still high enough to prevent the induction of IL-17 production. The latter suggestion is currently tested in our Institute.
Our studies show also the comparison of CsA and MP in their efficacy to
block PMA/ionomycin-induced production of IL-17 and TNF- (Fig. 6).
In these in vitro experiments, CsA is far more effective in blocking
both IL-17 and, to a lesser extent, TNF- than MP which even at
relatively high concentrations inhibits only 
50% of either cytokine
production. Although these results are preliminary, we should have them
in mind while considering therapeutic intervention into the cytokine
network blocking the effects of either TNF- (2, 3) or
IL-1ß (4). It is possible that combination of certain
immunosuppressive drugs (e.g., CsA) with new biological agents may
prove very effective.
In conclusion, we report high (RA) and undetectable (OA) levels of IL-17 that strongly correlate with the levels of IL-15 in synovial fluids of these patients. Moreover, our finding that IL-15 induces IL-17 production placed IL-17 in the cytokine network/cascade. Finally, we document high efficacy of CsA and MP in blocking IL-15-triggered IL-17 production in vitro. In addition, CsA is extremely, whereas MP is only partially effective in blocking PMA/ionomycin-triggered IL-17 production. Thus, if these in vitro observations apply to the situations in vivo, blocking IL-17 may represent yet another reason for using CsA in controlling unbalanced cytokine network.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Wlodzimierz Maslinski, Department of Pathophysiology and Immunology, Institute of Rheumatology, Spartanska 1, 02-637 Warsaw, Poland. E-mail address:
3 Abbreviations used in this paper: RA, rheumatoid arthritis; SFMCs, synovial fluid mononuclear cells; OA, osteoarthritis; MP, methylprednisolone; CsA, cyclosporin A.
Received for publication April 30, 1999. Accepted for publication December 20, 1999.
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References |
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, IL-1ß, IL-6) are elevated in serum of rheumatoid arthritis and juvenile arthritis patients. Immunol. Lett. 56:410.
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-chain administration prevents murine collagen-induced arthritis: a role for IL-15 in development of antigen-induced immunopathology. J. Immunol. 160:5654.2a protein blocks delayed-type hypersensitivity. J. Immunol. 160:5742., by human macrophages. J. Immunol. 160:3513. secretion by CD4+ T cells in the absence of TCR ligation. J. Immunol. 161:3408. chain in inflammatory synovitis. Arthritis Rheum. 42:S405.
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A. Saleh, L. Shan, A. J. Halayko, S. Kung, and A. S. Gounni Critical Role for STAT3 in IL-17A-Mediated CCL11 Expression in Human Airway Smooth Muscle Cells J. Immunol., March 15, 2009; 182(6): 3357 - 3365. [Abstract] [Full Text] [PDF]
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A. R. Mathers, B. M. Janelsins, J. P. Rubin, O. A. Tkacheva, W. J. Shufesky, S. C. Watkins, A. E. Morelli, and A. T. Larregina Differential Capability of Human Cutaneous Dendritic Cell Subsets to Initiate Th17 Responses J. Immunol., January 15, 2009; 182(2): 921 - 933. [Abstract] [Full Text] [PDF]
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 A. Webb, A. Johnson, M. Fortunato, A. Platt, T. Crabbe, M. I. Christie, G. F. Watt, S. G. Ward, and L. A. Jopling Evidence for PI-3K-dependent migration of Th17-polarized cells in response to CCR2 and CCR6 agonists J. Leukoc. Biol., October 1, 2008; 84(4): 1202 - 1212. [Abstract] [Full Text] [PDF]
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J. D. Isaacs Therapeutic T-cell manipulation in rheumatoid arthritis: past, present and future Rheumatology, October 1, 2008; 47(10): 1461 - 1468. [Abstract] [Full Text] [PDF]
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H Yamada, Y Nakashima, K Okazaki, T Mawatari, J-I Fukushi, N Kaibara, A Hori, Y Iwamoto, and Y Yoshikai Th1 but not Th17 cells predominate in the joints of patients with rheumatoid arthritis Ann Rheum Dis, September 1, 2008; 67(9): 1299 - 1304. [Abstract] [Full Text] [PDF]
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 W. Chi, X. Zhu, P. Yang, X. Liu, X. Lin, H. Zhou, X. Huang, and A. Kijlstra Upregulated IL-23 and IL-17 in Behcet Patients with Active Uveitis Invest. Ophthalmol. Vis. Sci., July 1, 2008; 49(7): 3058 - 3064. [Abstract] [Full Text] [PDF]
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V. Paunovic, H. P. Carroll, K. Vandenbroeck, and M. Gadina Signalling, inflammation and arthritis: Crossed signals: the role of interleukin (IL)-12, -17, -23 and -27 in autoimmunity Rheumatology, June 1, 2008; 47(6): 771 - 776. [Abstract] [Full Text] [PDF]
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 M. J. Lindemann, Z. Hu, M. Benczik, K. D. Liu, and S. L. Gaffen Differential Regulation of the IL-17 Receptor by {gamma}c Cytokines: INHIBITORY SIGNALING BY THE PHOSPHATIDYLINOSITOL 3-KINASE PATHWAY J. Biol. Chem., May 16, 2008; 283(20): 14100 - 14108. [Abstract] [Full Text] [PDF]
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 C. Badoual, G. Bouchaud, N. E. H. Agueznay, E. Mortier, S. Hans, A. Gey, F. Fernani, S. Peyrard, P. L. -Puig, P. Bruneval, et al. The Soluble {alpha} Chain of Interleukin-15 Receptor: A Proinflammatory Molecule Associated with Tumor Progression in Head and Neck Cancer Cancer Res., May 15, 2008; 68(10): 3907 - 3914. [Abstract] [Full Text] [PDF]
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 M. C. Lebre, S. L. Jongbloed, S. W. Tas, T. J.M. Smeets, I. B. McInnes, and P. P. Tak Rheumatoid Arthritis Synovium Contains Two Subsets of CD83-DC-LAMP- Dendritic Cells with Distinct Cytokine Profiles Am. J. Pathol., April 1, 2008; 172(4): 940 - 950. [Abstract] [Full Text] [PDF]
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H. Li, M. M. Nooh, M. Kotb, and F. Re Commercial peptidoglycan preparations are contaminated with superantigen-like activity that stimulates IL-17 production J. Leukoc. Biol., February 1, 2008; 83(2): 409 - 418. [Abstract] [Full Text] [PDF]
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K. S. Weber, M. J. Miller, and P. M. Allen Th17 Cells Exhibit a Distinct Calcium Profile from Th1 and Th2 Cells and Have Th1-Like Motility and NF-AT Nuclear Localization J. Immunol., February 1, 2008; 180(3): 1442 - 1450. [Abstract] [Full Text] [PDF]
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 D. T. Nardelli, S. M. Callister, and R. F. Schell Lyme Arthritis: Current Concepts and a Change in Paradigm Clin. Vaccine Immunol., January 1, 2008; 15(1): 21 - 34. [Full Text] [PDF]
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J. S. H. Gaston Cytokines in arthritis the 'big numbers' move centre stage Rheumatology, January 1, 2008; 47(1): 8 - 12. [Abstract] [Full Text] [PDF]
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 J. Moisan, R. Grenningloh, E. Bettelli, M. Oukka, and I-C. Ho Ets-1 is a negative regulator of Th17 differentiation J. Exp. Med., November 26, 2007; 204(12): 2825 - 2835. [Abstract] [Full Text] [PDF]
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Y. Yamaguchi, K. Fujio, H. Shoda, A. Okamoto, N. H. Tsuno, K. Takahashi, and K. Yamamoto IL-17B and IL-17C Are Associated with TNF-{alpha} Production and Contribute to the Exacerbation of Inflammatory Arthritis J. Immunol., November 15, 2007; 179(10): 7128 - 7136. [Abstract] [Full Text] [PDF]
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K. M. Hildner, P. Schirmacher, I. Atreya, M. Dittmayer, B. Bartsch, P. R. Galle, S. Wirtz, and M. F. Neurath Targeting of the Transcription Factor STAT4 by Antisense Phosphorothioate Oligonucleotides Suppresses Collagen-Induced Arthritis J. Immunol., March 15, 2007; 178(6): 3427 - 3436. [Abstract] [Full Text] [PDF]
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M. Umemura, A. Yahagi, S. Hamada, M. D. Begum, H. Watanabe, K. Kawakami, T. Suda, K. Sudo, S. Nakae, Y. Iwakura, et al. IL-17-Mediated Regulation of Innate and Acquired Immune Response against Pulmonary Mycobacterium bovis Bacille Calmette-Guerin Infection J. Immunol., March 15, 2007; 178(6): 3786 - 3796. [Abstract] [Full Text] [PDF]
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H.-R. Kim, M.-L. Cho, K.-W. Kim, J.-Y. Juhn, S.-Y. Hwang, C.-H. Yoon, S.-H. Park, S.-H. Lee, and H.-Y. Kim Up-regulation of IL-23p19 expression in rheumatoid arthritis synovial fibroblasts by IL-17 through PI3-kinase-, NF-{kappa}B- and p38 MAPK-dependent signalling pathways Rheumatology, January 1, 2007; 46(1): 57 - 64. [Abstract] [Full Text] [PDF]
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M I Koenders, L A B Joosten, and W B van den Berg Potential new targets in arthritis therapy: interleukin (IL)-17 and its relation to tumour necrosis factor and IL-1 in experimental arthritis Ann Rheum Dis, November 1, 2006; 65(suppl_3): iii29 - iii33. [Abstract] [Full Text] [PDF]
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M. S. Rahman, A. Yamasaki, J. Yang, L. Shan, A. J. Halayko, and A. S. Gounni IL-17A Induces Eotaxin-1/CC Chemokine Ligand 11 Expression in Human Airway Smooth Muscle Cells: Role of MAPK (Erk1/2, JNK, and p38) Pathways J. Immunol., September 15, 2006; 177(6): 4064 - 4071. [Abstract] [Full Text] [PDF]
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S.-A. Yoo, B.-H. Park, G.-S. Park, H.-S. Koh, M.-S. Lee, S. H. Ryu, K. Miyazawa, S.-H. Park, C.-S. Cho, and W.-U. Kim Calcineurin Is Expressed and Plays a Critical Role in Inflammatory Arthritis J. Immunol., August 15, 2006; 177(4): 2681 - 2690. [Abstract] [Full Text] [PDF]
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M. I. Koenders, E. Lubberts, F. A. J. van de Loo, B. Oppers-Walgreen, L. van den Bersselaar, M. M. Helsen, J. K. Kolls, F. E. Di Padova, L. A. B. Joosten, and W. B. van den Berg Interleukin-17 Acts Independently of TNF-{alpha} under Arthritic Conditions J. Immunol., May 15, 2006; 176(10): 6262 - 6269. [Abstract] [Full Text] [PDF]
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C. A. Amlong, D. T. Nardelli, S. H. Peterson, T. F. Warner, S. M. Callister, and R. F. Schell Anti-Interleukin-15 Prevents Arthritis in Borrelia-Vaccinated and -Infected Mice Clin. Vaccine Immunol., February 1, 2006; 13(2): 289 - 296. [Abstract] [Full Text] [PDF]
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H. Kidoya, M. Umemura, T. Kawabe, G. Matsuzaki, A. Yahagi, R. Imamura, and T. Suda Fas Ligand Induces Cell-Autonomous IL-23 Production in Dendritic Cells, a Mechanism for Fas Ligand-Induced IL-17 Production J. Immunol., December 15, 2005; 175(12): 8024 - 8031. [Abstract] [Full Text] [PDF]
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K. I. Happel, P. J. Dubin, M. Zheng, N. Ghilardi, C. Lockhart, L. J. Quinton, A. R. Odden, J. E. Shellito, G. J. Bagby, S. Nelson, et al. Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae J. Exp. Med., September 19, 2005; 202(6): 761 - 769. [Abstract] [Full Text] [PDF]
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E. Lubberts, P. Schwarzenberger, W. Huang, J. R. Schurr, J. J. Peschon, W. B. van den Berg, and J. K. Kolls Requirement of IL-17 Receptor Signaling in Radiation-Resistant Cells in the Joint for Full Progression of Destructive Synovitis J. Immunol., September 1, 2005; 175(5): 3360 - 3368. [Abstract] [Full Text] [PDF]
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M. I. Koenders, E. Lubberts, B. Oppers-Walgreen, L. van den Bersselaar, M. M. Helsen, F. E. Di Padova, A. M.H. Boots, H. Gram, L. A.B. Joosten, and W. B. van den Berg Blocking of Interleukin-17 during Reactivation of Experimental Arthritis Prevents Joint Inflammation and Bone Erosion by Decreasing RANKL and Interleukin-1 Am. J. Pathol., July 1, 2005; 167(1): 141 - 149. [Abstract] [Full Text] [PDF]
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 T. Ishizu, M. Osoegawa, F.-J. Mei, H. Kikuchi, M. Tanaka, Y. Takakura, M. Minohara, H. Murai, F. Mihara, T. Taniwaki, et al. Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis Brain, May 1, 2005; 128(5): 988 - 1002. [Abstract] [Full Text] [PDF]
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C. L. Langrish, Y. Chen, W. M. Blumenschein, J. Mattson, B. Basham, J. D. Sedgwick, T. McClanahan, R. A. Kastelein, and D. J. Cua IL-23 drives a pathogenic T cell population that induces autoimmune inflammation J. Exp. Med., January 18, 2005; 201(2): 233 - 240. [Abstract] [Full Text] [PDF]
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X. K. Liu, X. Lin, and S. L. Gaffen Crucial Role for Nuclear Factor of Activated T Cells in T Cell Receptor-mediated Regulation of Human Interleukin-17 J. Biol. Chem., December 10, 2004; 279(50): 52762 - 52771. [Abstract] [Full Text] [PDF]
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S. Ferrari-Lacraz, E. Zanelli, M. Neuberg, E. Donskoy, Y. S. Kim, X. X. Zheng, W. W. Hancock, W. Maslinski, X. C. Li, T. B. Strom, et al. Targeting IL-15 Receptor-Bearing Cells with an Antagonist Mutant IL-15/Fc Protein Prevents Disease Development and Progression in Murine Collagen-Induced Arthritis J. Immunol., November 1, 2004; 173(9): 5818 - 5826. [Abstract] [Full Text] [PDF]
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L. A. Lieberman, F. Cardillo, A. M. Owyang, D. M. Rennick, D. J. Cua, R. A. Kastelein, and C. A. Hunter IL-23 Provides a Limited Mechanism of Resistance to Acute Toxoplasmosis in the Absence of IL-12 J. Immunol., August 1, 2004; 173(3): 1887 - 1893. [Abstract] [Full Text] [PDF]
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M. Umemura, T. Kawabe, K. Shudo, H. Kidoya, M. Fukui, M. Asano, Y. Iwakura, G. Matsuzaki, R. Imamura, and T. Suda Involvement of IL-17 in Fas ligand-induced inflammation Int. Immunol., August 1, 2004; 16(8): 1099 - 1108. [Abstract] [Full Text] [PDF]
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M.-E. Miranda-Carus, A. Balsa, M. Benito-Miguel, C. Perez de Ayala, and E. Martin-Mola IL-15 and the Initiation of Cell Contact-Dependent Synovial Fibroblast-T Lymphocyte Cross-Talk in Rheumatoid Arthritis: Effect of Methotrexate J. Immunol., July 15, 2004; 173(2): 1463 - 1476. [Abstract] [Full Text] [PDF]
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 Y. Zhang, J. Xu, J. Levin, M. Hegen, G. Li, H. Robertshaw, F. Brennan, T. Cummons, D. Clarke, N. Vansell, et al. J. Pharmacol. Exp. Ther., April 1, 2004; 309(1): 348 - 355. [Abstract] [Full Text]
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D. O'Gradaigh and J. E. Compston T-cell involvement in osteoclast biology: implications for rheumatoid bone erosion Rheumatology, February 1, 2004; 43(2): 122 - 130. [Full Text] [PDF]
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C. A. Murphy, C. L. Langrish, Y. Chen, W. Blumenschein, T. McClanahan, R. A. Kastelein, J. D. Sedgwick, and D. J. Cua Divergent Pro- and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune Inflammation J. Exp. Med., December 15, 2003; 198(12): 1951 - 1957. [Abstract] [Full Text] [PDF]
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S. Nakae, A. Nambu, K. Sudo, and Y. Iwakura Suppression of Immune Induction of Collagen-Induced Arthritis in IL-17-Deficient Mice J. Immunol., December 1, 2003; 171(11): 6173 - 6177. [Abstract] [Full Text] [PDF]
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W. H. Faour, A. Mancini, Q. W. He, and J. A. Di Battista T-cell-derived Interleukin-17 Regulates the Level and Stability of Cyclooxygenase-2 (COX-2) mRNA through Restricted Activation of the p38 Mitogen-activated Protein Kinase Cascade: ROLE OF DISTAL SEQUENCES IN THE 3'-UNTRANSLATED REGION OF COX-2 mRNA J. Biol. Chem., July 11, 2003; 278(29): 26897 - 26907. [Abstract] [Full Text] [PDF]
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 M. A. Burchill, D. T. Nardelli, D. M. England, D. J. DeCoster, J. A. Christopherson, S. M. Callister, and R. F. Schell Inhibition of Interleukin-17 Prevents the Development of Arthritis in Vaccinated Mice Challenged with Borrelia burgdorferi Infect. Immun., June 1, 2003; 71(6): 3437 - 3442. [Abstract] [Full Text] [PDF]
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 S. Nakae, S. Saijo, R. Horai, K. Sudo, S. Mori, and Y. Iwakura IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist PNAS, May 13, 2003; 100(10): 5986 - 5990. [Abstract] [Full Text] [PDF]
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Y. Chen, P. Thai, Y.-H. Zhao, Y.-S. Ho, M. M. DeSouza, and R. Wu Stimulation of Airway Mucin Gene Expression by Interleukin (IL)-17 through IL-6 Paracrine/Autocrine Loop J. Biol. Chem., May 2, 2003; 278(19): 17036 - 17043. [Abstract] [Full Text] [PDF]
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 M. Numasaki, J.-i. Fukushi, M. Ono, S. K. Narula, P. J. Zavodny, T. Kudo, P. D. Robbins, H. Tahara, and M. T. Lotze Interleukin-17 promotes angiogenesis and tumor growth Blood, April 1, 2003; 101(7): 2620 - 2627. [Abstract] [Full Text] [PDF]
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S. Ferretti, O. Bonneau, G. R. Dubois, C. E. Jones, and A. Trifilieff IL-17, Produced by Lymphocytes and Neutrophils, Is Necessary for Lipopolysaccharide-Induced Airway Neutrophilia: IL-15 as a Possible Trigger J. Immunol., February 15, 2003; 170(4): 2106 - 2112. [Abstract] [Full Text] [PDF]
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 P. W. Hellings, A. Kasran, Z. Liu, P. Vandekerckhove, A. Wuyts, L. Overbergh, C. Mathieu, and J. L. Ceuppens Interleukin-17 Orchestrates the Granulocyte Influx into Airways after Allergen Inhalation in a Mouse Model of Allergic Asthma Am. J. Respir. Cell Mol. Biol., January 1, 2003; 28(1): 42 - 50. [Abstract] [Full Text] [PDF]
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R L van Bezooijen, L van der Wee-Pals, S E Papapoulos, and C W G M Lowik Interleukin 17 synergises with tumour necrosis factor {alpha} to induce cartilage destruction in vitro Ann Rheum Dis, October 1, 2002; 61(10): 870 - 876. [Abstract] [Full Text] [PDF]
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M. R. Kim, R. Manoukian, R. Yeh, S. M. Silbiger, D. M. Danilenko, S. Scully, J. Sun, M. L. DeRose, M. Stolina, D. Chang, et al. Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production Blood, September 18, 2002; 100(7): 2330 - 2340. [Abstract] [Full Text] [PDF]
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M. Kurowska, W. Rudnicka, E. Kontny, I. Janicka, M. Chorazy, J. Kowalczewski, M. Ziolkowska, S. Ferrari-Lacraz, T. B. Strom, and W. Maslinski Fibroblast-Like Synoviocytes from Rheumatoid Arthritis Patients Express Functional IL-15 Receptor Complex: Endogenous IL-15 in Autocrine Fashion Enhances Cell Proliferation and Expression of Bcl-xL and Bcl-2 J. Immunol., August 15, 2002; 169(4): 1760 - 1767. [Abstract] [Full Text] [PDF]
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P J Koshy, N Henderson, C Logan, P F Life, T E Cawston, and A D Rowan Interleukin 17 induces cartilage collagen breakdown: novel synergistic effects in combination with proinflammatory cytokines Ann Rheum Dis, August 1, 2002; 61(8): 704 - 713. [Abstract] [Full Text] [PDF]
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F. Benchetrit, A. Ciree, V. Vives, G. Warnier, A. Gey, C. Sautes-Fridman, F. Fossiez, N. Haicheur, W. H. Fridman, and E. Tartour Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism Blood, March 15, 2002; 99(6): 2114 - 2121. [Abstract] [Full Text] [PDF]
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A. Yamashita, Y. Yonemitsu, S. Okano, K. Nakagawa, Y. Nakashima, T. Irisa, Y. Iwamoto, Y. Nagai, M. Hasegawa, and K. Sueishi Fibroblast Growth Factor-2 Determines Severity of Joint Disease in Adjuvant-Induced Arthritis in Rats J. Immunol., January 1, 2002; 168(1): 450 - 457. [Abstract] [Full Text] [PDF]
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M. Kawaguchi, L. F. Onuchic, X.-D. Li, D. M. Essayan, J. Schroeder, H.-Q. Xiao, M. C. Liu, G. Krishnaswamy, G. Germino, and S.-K. Huang Identification of a Novel Cytokine, ML-1, and Its Expression in Subjects with Asthma J. Immunol., October 15, 2001; 167(8): 4430 - 4435. [Abstract] [Full Text] [PDF]
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E. Lubberts, L. A. B. Joosten, B. Oppers, L. van den Bersselaar, C. J. J. Coenen-de Roo, J. K. Kolls, P. Schwarzenberger, F. A. J. van de Loo, and W. B. van den Berg IL-1-Independent Role of IL-17 in Synovial Inflammation and Joint Destruction During Collagen-Induced Arthritis J. Immunol., July 15, 2001; 167(2): 1004 - 1013. [Abstract] [Full Text] [PDF]
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M. C. Honorati, R. Meliconi, L. Pulsatelli, S. Cane, L. Frizziero, and A. Facchini High in vivo expression of interleukin-17 receptor in synovial endothelial cells and chondrocytes from arthritis patients Rheumatology, May 1, 2001; 40(5): 522 - 527. [Abstract] [Full Text] [PDF]
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E. Chklovskaia, C. Nissen, L. Landmann, C. Rahner, O. Pfister, and A. Wodnar-Filipowicz Cell-surface trafficking and release of flt3 ligand from T lymphocytes is induced by common cytokine receptor {gamma}-chain signaling and inhibited by cyclosporin A Blood, February 15, 2001; 97(4): 1027 - 1034. [Abstract] [Full Text] [PDF]
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T. A. Fehniger and M. A. Caligiuri Interleukin 15: biology and relevance to human disease Blood, January 1, 2001; 97(1): 14 - 32. [Full Text] [PDF]
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F. Luzza, T. Parrello, G. Monteleone, L. Sebkova, M. Romano, R. Zarrilli, M. Imeneo, and F. Pallone Up-Regulation of IL-17 Is Associated with Bioactive IL-8 Expression in Helicobacter pylori-Infected Human Gastric Mucosa J. Immunol., November 1, 2000; 165(9): 5332 - 5337. [Abstract] [Full Text] [PDF]
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) were measured by
ELISA. – – – –, Detection limits of the assays.
·····, Mean value of each group. Statistical
comparison between RA (n = 15) and OA
(n = 8) patients is shown as a p
value; NS = not significant (two-tailed Mann-Whitney
U test).
