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Departments of Immunology and Rheumatology, Hôpital Edouard Herriot and Laboratoire d’ Immuno-Virologie Unité Mixte de Recherche, Centre National de la Recherche Scientifique (CNRS) 5537, Faculté de Médecine Laennec, Lyon;
Schering-Plough Laboratory for Immunological Research, Dardilly; and
CNRS Unité de Recherche Associée (URA) 1456, Université de Bordeaux II, Bordeaux, France
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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appear to play a pivotal role in local activation leading to
joint destruction (2). They interact with synoviocytes to produce
mediators of inflammation such as PGE2, degrading enzymes
such as collagenase, and other cytokines including
granulocyte/macrophage (GM)-CSF, IL-6, and leukemia inhibitory factor
(LIF) (3, 4, 5, 6, 7, 8).
Whereas T cells represent a large proportion of the inflammatory cells
invading the synovial tissue, T cell-derived cytokines are less
abundant in the joint than cytokines produced by the other cell types
described above (9, 10). In particular, the reduced production of IL-4
may contribute to uncontrolled inflammation (11). A similar conclusion
was reached for IL-10 and IL-13 (12). These cytokines, also defined as
Th2 cytokines (13), have thus been classified as anti-inflammatory
on the basis of their inhibitory effect on the production of IL-1,
TNF-, IL-6, and IL-8 by monocytes and synovium samples (11, 12, 14, 15, 16, 17).
Other T cell-derived cytokines such as IFN-
, defined as Th1
cytokines (13), act in an opposite way, contributing to an inflammatory
pattern (17). For newly defined cytokines, such classification is still
pending. This is the case for IL-17, characterized recently as the
human counterpart of mouse CTLA-8. This CD4 T cell-derived cytokine was
found to directly activate fibroblasts and synoviocytes, leading to the
production of IL-6, IL-8, PGE2, and granulocyte-CSF (18).
In addition, IL-17 was shown to sustain the maturation CD34-hemopoietic
progenitors into neutrophils when cultured with fibroblasts (19). In
keeping with its effect during inflammatory conditions, IL-17 was shown
to have an enhancing effect on nitric oxide production by
cartilage (20).
As this cytokine is produced only by activated T cells, we investigated the consequences of monocyte and T cell interaction on synoviocytes by looking at the effect of the T cell-derived cytokine IL-17 and the monocyte-derived cytokine IL-1 on cytokine production by synoviocytes. This was further studied in the presence of the regulatory cytokines IL-4, IL-13, and IL-10.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Purified Escherichia coli human rIL-4 (107 U/mg), rIL-10 (106 U/mg), rIL-13 (9.5 106 U/mg), and rIL-17 were from Schering-Plough Research Institute (Kenilworth, NJ). Human rIL-1ß (2 x 108 U/mg) was purchased from Sigma (St. Louis, MO).
Synovium samples and synoviocyte cultures
Rheumatoid synovium samples were obtained according to the
revised criteria of the American College of Rheumatology (21) from
patients with RA who were undergoing knee or wrist synovectomy or joint
replacement. Synovium piece cultures were performed as already
described (11). Briefly, fat and fibrous tissues were removed, and the
synovium was cut into small pieces with a volume of approximately 5
mm3. Pieces of synovium were cultured in triplicate in
complete medium made of -MEM medium (Life Technologies, Grand
Island, NY) with 2 mM L-glutamine, 100 U/ml penicillin, 50
mg/ml gentamicin, 20 mM HEPES buffer, and 10% FCS. Cultures were
performed at 37°C in a 5% CO2/95%-air humidified
environment.
To isolate synoviocytes, synovium pieces were finely minced and digested with 4 mg/ml collagenase (Worthington, Freehold, NJ) in PBS-DMEM (Life Technologies) for 2 to 3 h at 37°C (7). After centrifugation, cells were suspended in complete medium and cultured in 100-mm culture petri dishes. After 48 h, nonadherent cells were removed. Adherent cells were cultured in complete medium, and at confluence were trypsinized and passaged in 150-cm2 culture flasks. Synoviocytes were used between passage 3 and 8. At this time, they were a homogenous population of fibroblast-like cells, negative for the expression of CD1, CD3, CD19, CD14, and HLA-DR, and positive for the expression of CD10, CD44, and CD54, as determined by FACS analysis, using FITC-conjugated mAbs from Becton Dickinson (Mountain View, CA).
To obtain culture supernatants, synoviocytes were plated in 96-well dishes at 104 cells/well in 200 µl of complete medium. The cytokines to be tested were added at the onset of the culture. Supernatants were collected after 7 days of culture.
Measurement of LIF and IL-6 levels
IL-6 levels were measured by two-site sandwich ELISA as previously described (22). Briefly, supernatants or serial dilutions of IL-6 standards (Schering-Plough Research Institute) were incubated for 60 min at 37°C in 96-well microtiter plates (Nunc, Roskilde, Denmark), coated overnight at 4°C with mouse 39C3 anti-IL-6 mAb (1 µg/ml), and saturated for 90 min at 20°C with PBS 5% BSA. After washing, a biotinylated mouse anti-IL-6 mAb (1 µg/ml) was added and incubated for 90 min at 20°C. After subsequent incubation with peroxidase-coupled streptavidin and revelation with orthophenylenediamine (Sigma), the plates were read at 492 nm.
LIF levels were also measured by a two-site sandwich ELISA using two monoclonal anti-LIF Abs (23). Mouse 1F10 anti-human LIF mAb was used for coating and biotinylated mouse 7D2 anti-human LIF mAb for detection. After subsequent incubation with a streptavidin-peroxidase complex and revelation with OPD, the ODs were measured at 492 nm.
Biologic assay for IL-17
Synoviocytes (104 cells/well) were incubated in
96-well plates in a final volume of 200 µl of their respective
complete medium. Samples were preincubated at 37°C for 30 min with 1
µg/ml of the anti-IL-17 mAb5 (Schering-Plough Research
Institute). mAb5 is a mouse IgG1 obtained after immunization with human
rIL-17. 1 µg/ml of mAb5 was able to completely inhibit the IL-6
production induced by 50 ng/ml of IL-17, whereas the irrelevant mAb MX1
had no effect. This Ab had no effect on the action of IL-1, TNF-,
GM-CSF, or M-CSF (19). Following the preincubation step, IL-17 (50
ng/ml) or a 1:10 dilution supernatant (with or without anti-IL-17)
was added at the onset of the culture for a 12-h incubation. Plates
were washed before addition of fresh medium. Supernatants were
collected after 48 h and stored at -20°C until cytokine
assays.
Statistical analysis
Results were expressed as mean ± SEM of n separate experiments. Differences between IL-4- or IL-13- or IL-10-treated groups and the control group were compared with nonparametric Wilcoxon paired t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We investigated whether IL-6 production by synoviocytes could be
modulated by the monocyte-derived cytokine IL-1ß and by the T
cell-derived cytokine IL-17. Synovial fibroblasts were incubated with
different concentrations of IL-1 and IL-17. After 7 days of culture,
supernatants were collected and assayed for IL-6 production by ELISA.
When IL-17 at concentrations ranging from 0.01 to 1000 ng/ml and IL-1
at concentrations ranging from 0.01 to 1000 pg/ml were used alone, IL-6
production was increased in a dose-dependent manner (Fig. 1
A). IL-1ß (100
pg/ml) induced a 33-fold increase of IL-6 production, while IL-17 (10
ng/ml) showed a lesser effect (17-fold increase) (Fig. 1A).
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B where synovial fibroblasts were incubated with
combinations of low concentrations of IL-1 (1 and 10 pg/ml) and IL-17
(1, 5, and 10 ng/ml). In particular, synergy was best observed with 1
ng/ml of IL-17 and 1 pg/ml of IL-1, which had no effect on IL-6
production when used alone. In time course studies, this synergistic
effect was seen as early as 24 h after culture initiation (data
not shown). Effect of IL-17 on LIF production by RA synoviocytes
Similarly, we investigated how LIF production by synoviocytes
could be modulated by IL-1ß and IL-17 (Fig. 2). When IL-17 at concentrations ranging
from 0.01 to 1000 ng/ml and IL-1 at concentrations ranging from 0.01 to
1000 pg/ml were used alone, LIF production was increased in a
dose-dependent manner (Fig. 2A). IL-1ß (100 pg/ml)
induced a 10-fold increase of LIF production, while IL-17 (10 ng/ml)
showed a lesser effect (4-fold increase).
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A). This is further demonstrated in
Figure 2B where synoviocytes incubated with low
concentrations of IL-1 (1–10 pg/ml) and IL-17 (1–10 ng/ml) in
combination produced more LIF than the synoviocytes incubated with each
cytokine separately, indicating an additive effect. In time course
studies, this additive effect was observed as early as 12 to 24 h
after initiation of culture (data not shown). Combined together, these results indicate that cytokines produced by monocytes (IL-1) and T cells (IL-17) can act together on synoviocytes at the low concentrations that can be expected to be present in vivo.
Regulation by IL-4, IL-13, and IL-10 of IL-6 and LIF production by RA synoviocytes induced by IL-1 and IL-17
IL-4, IL-13, and IL-10 were tested for their effect on the
secretion of IL-6 by synoviocytes stimulated with optimal
concentrations of IL-1ß and IL-17, alone and in combination. Levels
measured after 7 days of culture are presented in Table I. Addition of IL-4 and IL-13 used alone
at the onset of culture increased the spontaneous secretion of IL-6 by
4.5-fold. This effect was much lower than that of IL-1 as well as that
of IL-17. However, with stimulated cells, a modest 30% enhancing
effect of IL-4 and IL-13 was found on IL-6 production by IL-17-,
IL-1ß-, or IL-1ß plus IL-17-stimulated synoviocytes. In contrast,
IL-10 had rather a modest inhibitory effect on activated synoviocytes.
This effect was less when IL-1ß and IL-17 were combined.
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, and as opposed to
the effect on IL-6, IL-4 and IL-13 reduced LIF production by
unstimulated synoviocytes with a mean inhibition of 60 and 77%,
respectively. Similar inhibitory effect was found with IL-1ß- or
IL-17-stimulated synoviocytes. This effect was less important when
IL-1ß and IL-17 were both added at the onset of culture. In contrast,
IL-10 had no effect on LIF production.
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). Addition of IL-4 and IL-13, but
not IL-10, increased the spontaneous secretion of IL-6. The enhancing
effect of IL-4 or IL-13 was more important on IL-17 or IL-17 plus
IL-1ß stimulation. For each of these conditions, IL-4 was in general
more potent than IL-13. In contrast, IL-10 had no effect on IL-6
production by synoviocytes, except for an inhibitory effect on IL-17
plus IL-1ß-stimulated synoviocytes.
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. Similar
inhibitory effects of IL-4 and IL-13 were found with IL-17- or
IL-1ß-stimulated or unstimulated synoviocytes. This inhibition was
less important when the two cytokines were combined. In contrast, IL-10
had no effect on LIF production by stimulated or unstimulated
synoviocytes.
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It was important to extend these results to natural IL-17 produced
by RA synovium. To test its effect on synoviocytes, the biologic
activity of IL-17 present in supernatants from RA synovium pieces was
measured (Table III). Supernatants
collected after 1 wk of culture of RA synovium pieces were preincubated
with and without blocking anti-IL-17 mAb before being tested on
synoviocytes. As a positive control, the IL-6-inducing effect of
rIL-17, but not IL-1, was completely blocked. A 50% reduction of the
induction of IL-6 and LIF production by RA synovium supernatants could
be specifically blocked by anti-IL-17 mAb 5, but not by an
isotype-matched irrelevant mAb, MX1.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1 interact with synoviocytes, leading to the production
of other cytokines such as IL-6, GM-CSF, and LIF (2). Contrasting with
the abundance of monocyte and synoviocyte-derived proinflammatory
cytokines, T cell-derived cytokines are difficult to detect in RA
synovium (9, 10). The objective of the present report was to examine the effect of IL-17, a specific T cell-derived cytokine, on synoviocytes in the presence of proinflammatory and anti-inflammatory cytokines. This allowed the study of the contribution of soluble factors in the interaction between T cells and synoviocytes.
IL-17 appears to be a proinflammatory cytokine produced by the RA synovium
IL-17 has been shown to activate the transcription nuclear factor
NF-
B and to induce the production/expression of IL-6, IL-8,
PGE2, G-CSF, and ICAM-1 in fibroblasts and the
production of nitric oxide by cartilage (18, 19, 20). Such effects are
shared with proinflammatory cytokines such as TNF- and IL-1. In the
context of inflammation, IL-17 is of interest because it acts directly
on various mesenchymal cells including chondrocytes and synoviocytes.
Indeed, in RA synovium, T cells are in close contact with monocytes and
fibroblasts. Thus it can be expected that factors produced by these
cell types act in concert on the resident cells. Indeed, molecules
involved in monocyte-synoviocyte interactions leading to enhanced
cytokine production have been clarified (25). Here, we show a
spontaneous production of biologically active IL-17 by cultures of RA
synovium pieces. Results obtained with a blocking anti-IL-17 Ab
indicate that IL-17 contributes to 
50% of the IL-6- or LIF-inducing
activity present in these supernatants. As a control, supernatants of
cultures of osteoarthritis synovium, which contain a reduced T cell
infiltrate, did not contain such IL-17-related activity (data not
shown).
IL-17 increases IL-1 effect on cytokine production by synoviocytes
The results indicate that the combination of the most potent monocyte-derived cytokine on synoviocytes, namely IL-1, and IL-17 strongly increases their cytokine production. When used alone, both IL-1ß and IL-17 induced IL-6 and LIF production by synovial fibroblasts in a dose-dependent manner. However, the effect of IL-17 was always less than that of IL-1.
These results were first obtained with optimal concentrations, which
may not represent the situation found in vivo. Accordingly, stimulation
was performed using low concentrations of IL-17 (1 ng/ml) and IL-1ß
(1 pg/ml) in combination. In such cultures, a synergistic effect of
IL-1 and IL-17 was observed on the production of IL-6, whereas an
additive effect was observed for LIF production. Similarly, whereas
neither IL-17 nor TNF- alone had any effect on the secretion of
GM-CSF, the combination of the two cytokines induced its production by
synoviocytes (19). In keeping with the in vivo relevance, these results
indicate that cytokines produced by monocytes (IL-1 or TNF-) and T
cells (IL-17) can act together on synoviocytes at the low levels that
can most probably be achieved in vivo. Such additive or even
synergistic effects explain the important reduction of the IL-6- and
LIF-inducing activity present in RA synovium supernatants with a
blocking anti-IL-17 Ab (Table III).
The mode of action of IL-17 on IL-1 effect remains to be clarified. A
differential effect on the induction of cytokine receptors may lead to
synergy. Indeed, the combination of IFN- and TNF- was found to
induce TNF-R expression, leading to increased response to TNF-
(26). Similar findings were obtained for the effect of IL-10 on IL-2R
expression by B cells (27). Such additive or synergistic effects could
be expected because the respective IL-1 and IL-17 receptors appear to
belong to different families (28). A complete characterization of the
components of the multichain IL-17R is in progress. Further studies
will thus be required to clarify the molecular basis of the interaction
between IL-1 and IL-17.
IL-17 acts as a Th1 cytokine
The proinflammatory effects of IL-17 suggest its classification as
a Th1 cytokine. This includes its effects on synoviocytes and the
maturation of neutrophils. Most of the T cell clones derived from RA
synovium have been classified as Th1 (29). Our recent studies suggest
that some IFN--producing RA synovium T cell clones also produce
biologically active IL-17 (unpublished data). Such findings, combined
with the demonstration of IL-17 production by RA synovium, are in line
with the classification of IL-17 as a Th1 cytokine. This subset of T
cells can then act directly on mesenchymal cells, leading to an
increased proinflammatory pattern and mediating matrix destruction
(20). It could be expected that such a concept also applies to other
Th1-mediated chronic diseases such as multiple sclerosis, psoriasis,
and diabetes (17). The exact proportion of IL-17-producing T cells and
their function remain to be determined. Conversely, control of such an
effect may lead to a therapeutic anti-inflammatory property.
Effects of Th2 cytokines
The Th2 cytokines IL-4, IL-13, and IL-10 have been classified as
anti-inflammatory on the basis of their inhibitory effect on the
production of IL-1, TNF-, IL-6, and IL-8 by monocytes and also by
synovium targets (11, 12, 14, 15, 16, 17). We studied the effects of these
cytokines on the production of IL-6 and LIF by RA synoviocytes
stimulated by IL-1 and IL-17. Both IL-4 and IL-13 enhanced by a modest
30% the IL-1- and IL-17-induced production of IL-6. In contrast, they
inhibited the production of LIF by 60 to 70%. IL-13 was in general
less potent than IL-4. The enhancing effect of IL-4 or IL-13 was more
potent with low concentrations of IL-17 than with IL-1ß.
Effects of IL-10
Surprisingly, the effects of IL-10 on IL-6 and LIF production were limited, in line with previous reports (7). IL-10 had no effect on LIF production, and a modest inhibitory effect of IL-6 production was found in response to IL-17 and/or IL-1. This is in contrast with its potent inhibitory effect on the secretion of proinflammatory cytokines by monocytes (15). Endogenous IL-10 has been shown to be produced by RA synovium acting as an anti-inflammatory cytokine (12). In addition, T cell clones from RA synovium also produced IL-10 (29). Because of its high endogenous production, addition of IL-10 had limited effect on cytokine production by RA synovium (30). On isolated synoviocytes, contrasting destructive and protective effects have been described. On one hand, IL-10 was found to down-regulate collagen I expression by fibroblasts while enhancing the production of collagenase and stromelysin (31). On the other hand, enhancement of tissue inhibitor of metalloproteinases (TIMP) production would limit destruction (32). In vivo studies will clarify the net effect of IL-10 on these targets.
Differential effect on LIF and IL-6 production
The opposite effects of IL-4 and IL-13 on IL-6 and LIF production further demonstrate the complexity of the cytokine network. Both IL-6 and LIF use the common gp130 receptor chain to activate target cells (33). However, they are differently regulated by IL-4 and IL-13 when combined with IL-17 and IL-1, findings that extend our previous results with IL-1 (7). This effect on synoviocytes contrast with the common inhibitory effect of IL-4 and IL-13 observed with monocytes and whole synovium (7, 14, 16, 17). In addition, it should be underlined that the classification of IL-6 as a proinflammatory cytokine remains a matter of debate. Through the induction of acute phase proteins, IL-6 also acts as a anti-inflammatory cytokine (34). Such an effect appears to be further enhanced by IL-4 and IL-13 when cells are first exposed to in vivo proinflammatory signals such as IL-17 and IL-1 combined at low concentrations. This would further enhance their anti-inflammatory properties at the site of inflammation.
In conclusion, IL-17 appears to be a T cell cytokine produced by the RA synovium, which acts directly on synoviocytes, leading to an enhanced proinflammatory secretion profile when combined with monocyte-derived signals. Accordingly, control of the production and action of IL-17 may represent a therapeutic target for reducing the enhancing effect of monocyte-derived cytokines. Among the available molecules of interest, some Th2 cytokines may control part of the consequences of such interaction.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. P. Miossec, Clinical Immunology Unit, Departments of Immunology and Rheumatology, Hôpital Edouard Herriot, 69437 Lyon Cedex 03, France. E-mail address:
3 Abbreviations used in this paper: RA, rheumatoid arthritis; LIF, leukemia inhibitory factor; GM-CSF, granulocyte/macrophage-CSF; M-CSF, macrophage-CSF.
Received for publication December 3, 1997. Accepted for publication February 25, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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G Chevrel, C Granet, and P Miossec Contribution of tumour necrosis factor {alpha} and interleukin (IL) 1{beta} to IL6 production, NF-{kappa}B nuclear translocation, and class I MHC expression in muscle cells: in vitro regulation with specific cytokine inhibitors Ann Rheum Dis, September 1, 2005; 64(9): 1257 - 1262. [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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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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 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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K. I. Happel, M. Zheng, E. Young, L. J. Quinton, E. Lockhart, A. J. Ramsay, J. E. Shellito, J. R. Schurr, G. J. Bagby, S. Nelson, et al. Cutting Edge: Roles of Toll-Like Receptor 4 and IL-23 in IL-17 Expression in Response to Klebsiella pneumoniae Infection J. Immunol., May 1, 2003; 170(9): 4432 - 4436. [Abstract] [Full Text] [PDF]
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E. Lubberts, L. van den Bersselaar, B. Oppers-Walgreen, P. Schwarzenberger, C. J. J. Coenen-de Roo, J. K. Kolls, L. A. B. Joosten, and W. B. van den Berg IL-17 Promotes Bone Erosion in Murine Collagen-Induced Arthritis Through Loss of the Receptor Activator of NF-{kappa}B Ligand/Osteoprotegerin Balance J. Immunol., March 1, 2003; 170(5): 2655 - 2662. [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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S. Aggarwal, N. Ghilardi, M.-H. Xie, F. J. de Sauvage, and A. L. Gurney Interleukin-23 Promotes a Distinct CD4 T Cell Activation State Characterized by the Production of Interleukin-17 J. Biol. Chem., January 10, 2003; 278(3): 1910 - 1914. [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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 S Fujino, A Andoh, S Bamba, A Ogawa, K Hata, Y Araki, T Bamba, and Y Fujiyama Increased expression of interleukin 17 in inflammatory bowel disease Gut, January 1, 2003; 52(1): 65 - 70. [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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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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G Chevrel, P Garnero, and P Miossec Addition of interleukin 1 (IL1) and IL17 soluble receptors to a tumour necrosis factor {alpha} soluble receptor more effectively reduces the production of IL6 and macrophage inhibitory protein-3{alpha} and increases that of collagen in an in vitro model of rheumatoid synoviocyte activation Ann Rheum Dis, August 1, 2002; 61(8): 730 - 733. [Abstract] [Full Text] [PDF]
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S. D. Hurst, T. Muchamuel, D. M. Gorman, J. M. Gilbert, T. Clifford, S. Kwan, S. Menon, B. Seymour, C. Jackson, T. T. Kung, et al. New IL-17 Family Members Promote Th1 or Th2 Responses in the Lung: In Vivo Function of the Novel Cytokine IL-25 J. Immunol., July 1, 2002; 169(1): 443 - 453. [Abstract] [Full Text] [PDF]
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 K. Hata, A. Andoh, M. Shimada, S. Fujino, S. Bamba, Y. Araki, T. Okuno, Y. Fujiyama, and T. Bamba IL-17 stimulates inflammatory responses via NF-kappa B and MAP kinase pathways in human colonic myofibroblasts Am J Physiol Gastrointest Liver Physiol, June 1, 2002; 282(6): G1035 - G1044. [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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M. Shimada, A. Andoh, K. Hata, K. Tasaki, Y. Araki, Y. Fujiyama, and T. Bamba IL-6 Secretion by Human Pancreatic Periacinar Myofibroblasts in Response to Inflammatory Mediators J. Immunol., January 15, 2002; 168(2): 861 - 868. [Abstract] [Full Text] [PDF]
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S. Aggarwal and A. L. Gurney IL-17: prototype member of an emerging cytokine family J. Leukoc. Biol., January 1, 2002; 71(1): 1 - 8. [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. Chabaud, G. Page, and P. Miossec Enhancing Effect of IL-1, IL-17, and TNF-{alpha} on Macrophage Inflammatory Protein-3{alpha} Production in Rheumatoid Arthritis: Regulation by Soluble Receptors and Th2 Cytokines J. Immunol., November 15, 2001; 167(10): 6015 - 6020. [Abstract] [Full Text] [PDF]
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 P. Ye, F. H. Rodriguez, S. Kanaly, K. L. Stocking, J. Schurr, P. Schwarzenberger, P. Oliver, W. Huang, P. Zhang, J. Zhang, et al. Requirement of Interleukin 17 Receptor Signaling for Lung Cxc Chemokine and Granulocyte Colony-Stimulating Factor Expression, Neutrophil Recruitment, and Host Defense J. Exp. Med., August 20, 2001; 194(4): 519 - 528. [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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Y. Yamamura, R. Gupta, Y. Morita, X. He, R. Pai, J. Endres, A. Freiberg, K. Chung, and D. A. Fox Effector Function of Resting T Cells: Activation of Synovial Fibroblasts J. Immunol., February 15, 2001; 166(4): 2270 - 2275. [Abstract] [Full Text] [PDF]
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C. Infante-Duarte, H. F. Horton, M. C. Byrne, and T. Kamradt Microbial Lipopeptides Induce the Production of IL-17 in Th Cells J. Immunol., December 1, 2000; 165(11): 6107 - 6115. [Abstract] [Full Text] [PDF]
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J. Witowski, K. Pawlaczyk, A. Breborowicz, A. Scheuren, M. Kuzlan-Pawlaczyk, J. Wisniewska, A. Polubinska, H. Friess, G. M. Gahl, U. Frei, et al. IL-17 Stimulates Intraperitoneal Neutrophil Infiltration Through the Release of GRO{alpha} Chemokine from Mesothelial Cells J. Immunol., November 15, 2000; 165(10): 5814 - 5821. [Abstract] [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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J. Dudler, N. Renggli-Zulliger, N. Busso, M. Lotz, and A. So Effect of interleukin 17 on proteoglycan degradation in murine knee joints Ann Rheum Dis, July 1, 2000; 59(7): 529 - 532. [Abstract] [Full Text]
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 C. J. Auernhammer and S. Melmed Leukemia-Inhibitory Factor--Neuroimmune Modulator of Endocrine Function Endocr. Rev., June 1, 2000; 21(3): 313 - 345. [Abstract] [Full Text]
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R. Schwandner, K. Yamaguchi, and Z. Cao Requirement of Tumor Necrosis Factor Receptor-Associated Factor (Traf)6 in Interleukin 17 Signal Transduction J. Exp. Med., April 3, 2000; 191(7): 1233 - 1240. [Abstract] [Full Text] [PDF]
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M. Ziolkowska, A. Koc, G. Luszczykiewicz, K. Ksiezopolska-Pietrzak, E. Klimczak, H. Chwalinska-Sadowska, and W. Maslinski High Levels of IL-17 in Rheumatoid Arthritis Patients: IL-15 Triggers In Vitro IL-17 Production Via Cyclosporin A-Sensitive Mechanism J. Immunol., March 1, 2000; 164(5): 2832 - 2838. [Abstract] [Full Text] [PDF]
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 H. Li, J. Chen, A. Huang, J. Stinson, S. Heldens, J. Foster, P. Dowd, A. L. Gurney, and W. I. Wood Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family PNAS, January 18, 2000; 97(2): 773 - 778. [Abstract] [Full Text] [PDF]
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 E. Tartour, F. Fossiez, I. Joyeux, A. Galinha, A. Gey, E. Claret, X. Sastre-Garau, J. Couturier, V. Mosseri, V. Vives, et al. Interleukin 17, a T-cell-derived Cytokine, Promotes Tumorigenicity of Human Cervical Tumors in Nude Mice Cancer Res., August 1, 1999; 59(15): 3698 - 3704. [Abstract] [Full Text] [PDF]
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 D Matusevicius, P Kivisakk, B He, N Kostulas, V Ozenci, S Fredrikson, and H Link Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis Multiple Sclerosis, April 1, 1999; 5(2): 101 - 104. [Abstract] [PDF]
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T. Aarvak, M. Chabaud, P. Miossec, and J. B. Natvig IL-17 Is Produced by Some Proinflammatory Th1/Th0 Cells But Not by Th2 Cells J. Immunol., February 1, 1999; 162(3): 1246 - 1251. [Abstract] [Full Text] [PDF]
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M. A. Antonysamy, W. C. Fanslow, F. Fu, W. Li, S. Qian, A. B. Troutt, and A. W. Thomson Evidence for a Role of IL-17 in Organ Allograft Rejection: IL-17 Promotes the Functional Differentiation of Dendritic Cell Progenitors J. Immunol., January 1, 1999; 162(1): 577 - 584. [Abstract] [Full Text] [PDF]
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Y. Shi, S. J. Ullrich, J. Zhang, K. Connolly, K. J. Grzegorzewski, M. C. Barber, W. Wang, K. Wathen, V. Hodge, C. L. Fisher, et al. A Novel Cytokine Receptor-Ligand Pair. IDENTIFICATION, MOLECULAR CHARACTERIZATION, AND IN VIVO IMMUNOMODULATORY ACTIVITY J. Biol. Chem., June 16, 2000; 275(25): 19167 - 19176. [Abstract] [Full Text] [PDF]
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