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The Journal of Immunology, 2006, 176: 6262-6269.
Copyright © 2006 by The American Association of Immunologists

Interleukin-17 Acts Independently of TNF-{alpha} under Arthritic Conditions1

Marije I. Koenders2,*, Erik Lubberts3,*, Fons A. J. van de Loo*, Birgitte Oppers-Walgreen*, Liduine van den Bersselaar*, Monique M. Helsen*, Jay K. Kolls, Franco E. Di Padova{dagger}, Leo A. B. Joosten* and Wim B. van den Berg*

* Experimental Rheumatology and Advanced Therapeutics, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; {dagger} Children’s Hospital of Pittsburgh, Department of Pediatric and Pulmonology, Pittsburgh, PA 15213; {ddagger} Novartis Institutes for Biomedical Research, Basel, Switzerland


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
The proinflammatory T cell cytokine IL-17 is a potent inducer of other cytokines such as IL-1 and TNF-{alpha}. The contribution of TNF in IL-17-induced joint inflammation is unclear. In this work we demonstrate using TNF-{alpha}-deficient mice that TNF-{alpha} is required in IL-17-induced joint pathology under naive conditions in vivo. However, overexpression of IL-17 aggravated K/BxN serum transfer arthritis to a similar degree in TNF-{alpha}-deficient mice and their wild-type counterparts, indicating that the TNF dependency of IL-17-induced pathology is lost under arthritic conditions. Also, during the course of the streptococcal cell wall-induced arthritis model, IL-17 was able to enhance inflammation and cartilage damage in the absence of TNF. Additional blocking of IL-1 during IL-17-enhanced streptococcal cell wall-induced arthritis did not reduce joint pathology in TNF-deficient mice, indicating that IL-1 is not responsible for this loss of TNF dependency. These data provide further understanding of the cytokine interplay during inflammation and demonstrate that, despite a strong TNF dependency under naive conditions, IL-17 acts independently of TNF under arthritic conditions.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Rheumatoid arthritis (RA)4 is an autoimmune disease of unknown etiology that is characterized by chronic inflammation of the joints leading to destruction of articular cartilage and bone. TNF-{alpha} and IL-1 are considered powerful targets in the treatment of RA because of their leading role in driving the enhanced production of cytokines, chemokines, and degradative enzymes. However, therapies that focus on blocking TNF-{alpha} or IL-1 are not always effective, implicating that other cytokines might be interesting as additional targets. Simultaneous inhibition of several proinflammatory cytokines has shown promising results in vitro (1, 2) and may be the best approach to increasing the percentage of responding patients as well as the responses of individual patients.

IL-17 is a proinflammatory T cell cytokine that could be considered a potential additional target in the treatment of RA. Concentrations of this cytokine are elevated in the synovium and the synovial fluids of RA patients (3, 4, 5, 6, 7). IL-17 is produced by activated and memory CD4+CD45RO+ T cells (4, 8, 9). The IL-17R is ubiquitously expressed (10, 11), and the many different target cells show various responses to IL-17. IL-17 stimulation leads to many different responses via the activation of the transcription factor NF-{kappa}B (12, 13, 14). Stromal cells such as fibroblasts, endothelial cells, and epithelial cells respond to IL-17 by the secretion of IL-6, LIF, G-CSF, and PGE2, and an increased expression of ICAM-1 (8, 15, 16). In addition, IL-17 induces the secretion of chemokines such as IL-8, MCP-1, and the growth-related oncogenes GRO-{alpha} and GRO-beta in fibroblasts (14, 17, 18).

IL-17 also strongly induces the secretion of TNF-{alpha} and IL-1 by macrophages (19). Interestingly, IL-17 can have both additive and synergistic effects with TNF-{alpha} and IL-1 on cytokine induction and tissue destruction (1, 2, 20, 21, 22), although it may have direct pathological effects as well. IL-17 enhances the TNF-{alpha}-induced synthesis of IL-1, IL-6, and IL-8 in skin and synovial fibroblasts (23) and the IL-1-induced production of IL-6 and LIF by RA synoviocytes (24). IL-17 has been shown to synergize with TNF-{alpha} and IL-1 in the up-regulation of NO and PGE2 production from osteoarthritic menisci (25) and in the induction of cartilage destruction in vitro (22, 26).

In experimental arthritis, a role for IL-17 has been clearly demonstrated in both the development stage and the progression stage. The induction of collagen-induced arthritis (CIA) is clearly suppressed in IL-17-deficient mice (27), and spontaneous arthritis no longer develops in IL-1R antagonist-deficient mice that also lack IL-17 (16). Using IL-17R-deficient mice, we recently showed that for acute streptococcal cell wall (SCW)-induced arthritis to switch to chronic destructive synovitis, IL-17 signaling is required (28, 29). Blocking of IL-17 showed the involvement of this T cell cytokine in joint inflammation and destruction after the onset of CIA (30, 31) and was strikingly effective in the T cell-mediated flare reaction of Ag-induced arthritis (32).

The induction of IL-1 and TNF-{alpha} by IL-17 and its additive and synergistic effects with these cytokines in vitro raised the question of which role these cytokines play in the IL-17-induced joint pathology. Local injection of IL-17 in a naive murine knee joint induces inflammation, cartilage proteoglycan depletion, and bone erosion (30, 33), and we recently showed that IL-17 overexpression in an arthritic joint significantly aggravates joint pathology (30, 34). Our previous studies showed no significant contribution of IL-1 in the IL-17-induced joint pathology (30, 34). However, the role of TNF remained to be elucidated. Therefore, in the present study we examined the relative dependency of TNF-{alpha} in the IL-17-induced joint inflammation and cartilage damage under naive and arthritic conditions in vivo.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Disclosures
 References
 
Animals

Homozygous TNF-{alpha}-deficient mice (129/Sv x C57BL/6 background) were obtained from Dr. G. Kollias (Alexander Fleming Biomedical Center, Vari, Greece) (35). Wild-type (WT) controls also shared the 129/Sv x C57BL/6 background. IL-1{alpha},beta-deficient mice (C57BL/6 background) were a gift of Dr. Y. Iwakura, Center of Experimental Medicine, University of Tokyo, Tokyo, Japan (36). Male C57BL/6 mice as WT controls for the IL-1-deficient mice were obtained from Elevage-Janvier. Because WT C57BL/6 did not differ from 129/Sv x C57BL/6 in IL-17-induced joint inflammation, only the data from the mixed background animals are shown. All mice were housed in filter top cages under specific pathogen-free conditions, and a standard diet and water were provided ad libitum. The mice were used between 10 and 12 wk of age and were housed in isolators after adenoviral injection. All animal procedures were approved by the institutional ethics committee of the Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

Materials

BSA was purchased from Sigma-Aldrich. RPMI 1640 medium, TRIzol reagent, oligo(dT) primers, and Moloney murine leukemia virus reverse transcriptase were obtained from Invitrogen Life Technologies. Primers were purchased from Biolegio. SYBR Green Master Mix was purchased from Applied Biosystems. Cytokine kits for the Luminex multianalyte system (BioPlex) were obtained from Bio-Rad.

Adenoviral (Ad) vectors

AdIL-17 was provided by J. K. Kolls, Children’s Hospital of Pittsburgh, PA, and was constructed as reported previously (37). Briefly, pACCmIL-17 vector was cotransfected with XbaI-restricted AdCMVLacZ DNA into 911 cells using calcium-phosphate precipitation. AdmIL-17 clones were screened by PCR, and protein production was confirmed by a murine IL-17 bioassay. The recombinant adenovirus contained <1 endotoxin unit/ml as measured by the Limulus amebocyte lysate assay (BioWhittaker). The replication-deficient empty viral vector AdDel70-3 (Adcontrol) was used as a control vector throughout the study.

Study protocol

Naive mice were anesthetized with isoflurane, and a small aperture in the skin of the knee was made for the intraarticular (i.a.) injection procedure. For local overexpression of IL-17, 107 PFU of the IL-17 expressing (AdIL-17) vector in 6 µl PBS was i.a. injected into the knee joint and, as a control, the control vector AdDel70-3 was used. Thereafter, mice were sacrificed by cervical dislocation, and knee joints were isolated at various time points.

Histology

Total knee joints of mice were isolated at days 2 and 10 after the injection of adenovirus. For standard histology, tissue was fixed for 4 days in 10% formalin, decalcified in 5% formic acid, and subsequently dehydrated and embedded in paraffin. Standard frontal section of 7 µm were mounted on Superfrost slides (Menzel-Gläser). H&E staining was performed to study joint inflammation. The severity of inflammation in the knee joints was scored on a scale of 0–3 (0, no cells; 1, mild cellularity; 2, moderate cellularity; and 3, maximal cellularity). To study proteoglycan depletion from the cartilage matrix, sections were stained with safranin O followed by counterstaining with fast green. Depletion of proteoglycan was determined by using an arbitrary scale of 0–3, ranging from a normal, fully stained cartilage to a destained cartilage fully depleted of proteoglycans. Histopathological changes in the knee joints were scored in the patella and femur/tibia regions on five semiserial sections of the joint spaced 70 µm apart. Scoring was performed in a blindfolded manner by two independent observers.

Cytokine measurements

To determine the levels of IL-1 and IL-17 in synovial washouts, patellae with surrounding soft tissue consisting of the tendon and synovium were dissected in a standardized manner (32). Patellae were cultured in RPMI 1640 medium containing 0.1% BSA and gentamicin (50 µg/ml) (200 µl/patella) for 1 h at room temperature. Thereafter, supernatant was harvested and centrifuged for 5 min at 1000 x g. Cytokine levels were determined using the Luminex multianalyte technology. The BioPlex system in combination with multiplex cytokine kits (Bio-Rad) was used. Cytokines were measured in 50 µl of patellae washout medium. The sensitivity of the multiplex kit was for IL-1beta 5 pg/ml and for IL-17 and 12.5 pg/ml, respectively.

SCW preparation and induction of SCW-induced arthritis

Streptococcus pyogenes T12 organisms were cultures overnight in Todd-Hewitt broth. Cells walls were prepared as described previously (38). The resulting 10,000 x g supernatant was used throughout the experiments. These preparations contained 11% muramic acid. Unilateral arthritis was induced by i.a. injection of 25 µg of SCW (rhamnose content) in 6 µl of pyrogen-free saline into the right knee joints of naive mice. As a control, PBS was injected into the left knee joint. To investigate the TNF-{alpha} dependency of IL-17-induced joint pathology under arthritic conditions, IL-17 was locally overexpressed in this model by the i.a. injection of 107 PFU of AdIL-17 or the control vector in the knee joint 18 h before the induction of arthritis by SCW. Two and ten days after the induction of arthritis by SCW, the effects on joint pathology were analyzed.

Induction of K/BxN serum transfer arthritis

KRN TCR transgenic mice were a gifts from Dr. C. Benoist and Dr. D. Mathis, Joslin Diabetes Center, Harvard Medical School, Boston, MA (39) and were maintained on a C57BL/6 background (K/B). Arthritic mice were obtained by crossing K/B with NOD/Lt (N) animals (K/BxN). Arthritic adult K/BxN mice were bled, and the sera were pooled. Recipient mice were injected with 240 µl i.p. on day 0. AdIL-17 or a control vector were injected i.a. 18 h before arthritis induction, and at day 10 knee and ankle joints were isolated for histological analysis.

Statistical analysis

Differences between experimental groups were tested using the Mann-Whitney U test unless stated otherwise. Values of p < 0.05 were considered significant. Results are expressed as the mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Disclosures
 References
 
IL-17-induced joint pathology in naive mice is dependent on TNF-{alpha}

Local overexpression of IL-17 using an adenoviral vector results in acute joint inflammation and cartilage proteoglycan depletion in the knee joint of naive mice (Fig. 1, A–C). Because IL-17 can induce the production of and act in synergy with TNF-{alpha} and IL-1beta, the dependency of these cytokines in IL-17-induced joint pathology was investigated. Therefore, IL-17 was locally overexpressed in the knee joint of naive mice deficient for either IL-1 (IL-1{alpha}beta–/–) or TNF-{alpha} (TNF-{alpha}–/–). Interestingly, TNF-{alpha}-deficiency resulted in marked suppression of IL-17-induced joint inflammation, because hardly any infiltrating cells could be found in the synovial layers (Fig. 1, A and D). In addition, the cartilage of TNF-{alpha}–/– mice was protected against IL-17-induced proteoglycan depletion (Fig. 1, B and D). However, in IL-1-deficient mice histological analysis showed a similar degree of joint inflammation and cartilage proteoglycan depletion as their WT controls (Fig. 1, A and B). In addition, synovial TNF levels were similar in IL-1{alpha}beta–/– and WT controls, suggesting that IL-17-induced TNF production is independent of IL-1 (Fig. 2A).


Figure 1
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  		FIGURE 1. TNF-{alpha} deficiency protects against IL-17-induced joint pathology. A and B, Histological scores for synovial inflammation (A) and cartilage proteoglycan (PG) depletion (B) in mice deficient for TNF-{alpha} (TNF–/–) or IL-1{alpha}beta (IL-1–/–) and their WT counterparts at days 2 and 10 after intraarticular injection of 107 PFU of AdIL-17. Synovial infiltrate and cartilage proteoglycan depletion were scored on a scale of 0–3. Results are the mean ± SEM; *, p < 0.005 vs WT mice by Mann-Whitney U test. C and D, Knee joint of a WT mouse (C) and a TNF–/– mouse (D) stained with safranin O 10 days after local IL-17 overexpression. Abbreviations: P, patella; F, femur; S, synovitis; C, cartilage; JS, joint space. Original magnification, x100.

 

Figure 2
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  		FIGURE 2. Synovial cytokine production after AdIL-17 overexpression. A, TNF levels are similar in IL-1-deficient (IL-1–/–) mice and their WT counterparts. B, IL-17 production is comparable in TNF-deficient (TNF–/–) mice and their WT counterparts. Mice were injected with 107 PFU of AdIL-17, and at different time points synovial washouts were made and measured using Luminex bead array. Results are the mean ± SEM.

 
Synovial IL-17 levels were comparable in TNF-{alpha}–/– and WT mice (Fig. 2B), indicating that TNF-{alpha} deficiency had no effect on CMV promoter-driven IL-17 production. In addition, intraarticular injections with rIL-17 protein also gave TNF-dependent responses, although IL-17 receptor expression was comparable in TNF–/– and WT mice (data not shown). Of note, IL-1beta protein levels in synovial washouts 2 days after overexpressing IL-17 showed that the expression of IL-1beta in TNF-{alpha}–/– mice was markedly suppressed compared with that in WT mice (23 ± 25 pg/ml for TNF–/– vs 155 ± 55 pg/ml for WT mice), suggesting a role for IL-17 upstream of IL-1. These data indicate a requirement for TNF-{alpha} and not for IL-1 in IL-17-induced joint pathology under naive conditions in vivo.

Loss of TNF-{alpha} dependency of IL-17-induced joint pathology under arthritic conditions

To study the role of TNF in IL-17-mediated joint pathology under arthritic conditions, we overexpressed the T cell factor IL-17 in two different acute inflammatory arthritis models: 1) the K/BxN serum transfer model mediated by FcR-binding immune complexes (40); and 2) SCW-induced arthritis dependent on TLR-activation and signaling through MyD88 (41). Both murine arthritis models are mediated by TNF as described previously (42, 43).

First, IL-17 was overexpressed in TNF-deficient mice during immune complex-mediated arthritis (Fig. 3). The K/BxN serum transfer model is usually restricted to wrists and ankles but also affected the knee joints when the control virus was locally injected (Fig. 3, A–G). TNF-deficient mice in the control virus group showed suppressed inflammation and cartilage damage in the knee joints (Fig. 3, A–E, and H), as was expected from previous studies showing TNF dependency of this arthritis model (42). Interestingly, overexpression of IL-17 clearly enhanced joint inflammation during immune complex arthritis in a TNF-independent manner (Fig. 3, A, B, I, and J). In addition, cartilage proteoglycan depletion, chondrocyte death, and cartilage surface erosion did not differ between TNF–/– mice and their WT counterparts during IL-17 enhanced arthritis (Fig. 3, C–E, I, and J). This result indicates that IL-17-mediated joint pathology lost its TNF dependency during the course of this K/BxN serum transfer model.


Figure 3
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  		FIGURE 3. IL-17 overexpression enhances K/BxN serum transfer arthritis in the knee joint independently of TNF-{alpha}. At day 10 of arthritis, knee joints were scored macroscopically (A) on a scale of 0–2, and histology (B–E) was scored on a scale of 0–3. Histology was scored for infiltrating cells (B), cartilage proteoglycan (PG) depletion (C), chondrocyte death (D), and cartilage surface erosions (E) in mice deficient for TNF-{alpha} (TNF–/–) and their WT counterparts at day 10 after i.a. injection of 107 PFU of AdIL-17 or a control virus (AdC) during K/BxN serum transfer arthritis. Results are the mean ± SEM; *, p < 0.005 vs WT mice by Mann-Whitney U test. F–J, Knee joints of WT (F, G, and I) and TNF–/– (H and J) mice 10 days after K/BxN serum transfer with or without IL-17 or control viruses, stained with safranin O. Abbreviations: P, patella; F, femur; S, synovitis; C, cartilage; JS, joint space. Original magnification, x100.

 
Next, we examined whether the TNF-{alpha} dependency of IL-17-induced joint pathology could be bypassed by other arthritogenic stimuli as well. To this end we used SCW fragments as a costimulus. Histological analysis revealed that overexpression of IL-17 in the presence of SCW-induced arthritis resulted in an elevation of synovial inflammation and enhanced cartilage proteoglycan depletion (Table I). Consistent with our data from the immune complex model, subsequent studies in TNF-deficient mice revealed that IL-17 was able to enhance SCW-induced joint pathology in the absence of TNF-{alpha} (Fig. 4). After local injection of AdIL-17 and subsequent induction of arthritis by SCW, both joint inflammation and cartilage proteoglycan depletion were comparable in TNF-deficient mice and their WT controls (Fig. 4), which is in striking contrast to the naive situation (Fig. 1).


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  		Table I. IL-17 aggravates joint inflammation and cartilage proteoglycan (PG) depletion during SCW-induced arthritisa

 

Figure 4
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  		FIGURE 4. IL-17-induced joint pathology lost its TNF dependency during SCW-induced arthritis. Histological scores for infiltrate (A) and cartilage PG depletion (B) in mice deficient for TNF-{alpha} (TNF–/–) and their wild-types WT counterparts at various time points after intraarticular injection of 107 PFU of AdIL-17 and subsequent induction of arthritis by SCW. Synovial infiltrate and cartilage proteoglycan depletion were scored on a scale of 0–3. Results are the mean ± SEM; *, p < 0.0005 vs wild-type mice by Mann-Whitney U test.

 
In summary, Fig. 5 clearly shows that, under naive conditions, IL-17-induced joint pathology is almost completely dependent on TNF and that this relative TNF dependency is bypassed in two different murine arthritis models. These data show circumvention of TNF-{alpha} dependency of IL-17-induced joint pathology under arthritic conditions in vivo.


Figure 5
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  		FIGURE 5. IL-17 acts independently of TNF under arthritic conditions. Relative histological scores for joint inflammation and cartilage Proteoglycan (PG) depletion at day 10 in TNF-deficient mice (TNF–/–) and their WT counterparts after IL-17 overexpression under naive conditions and under arthritic conditions, the K/BxN serum transfer model, and SCW-induced arthritis. Note the TNF dependency of IL-17-induced joint pathology under naive conditions and the loss of TNF dependency during experimental arthritis models. For raw data of histological scores, see Figs. 1, 3, and 4. Results are the mean ± S.E.M as a percentage of wild-type mice; *, p < 0.01 vs WT mice by Mann-Whitney U test.

 
Loss of TNF-{alpha} dependency of IL-17-induced joint pathology during SCW-induced arthritis cannot be explained by the presence of IL-1

Previous studies have shown that IL-1 plays an important role in SCW-induced arthritis (34, 41, 44) and during the K/BxN serum transfer arthritis model (42). It is also known that IL-17 can act in synergy with IL-1, both in the process of inflammation and in cartilage degradation (21, 24, 25, 26). To investigate whether the loss of the TNF dependency of IL-17-induced joint pathology under arthritic conditions is caused by the presence of IL-1 and synergistic interactions between IL-1 and IL-17, we overexpressed IL-17 during SCW-induced arthritis in TNF-{alpha}–/– and WT mice and, in addition, blocked IL-1 by administration of neutralizing Abs for IL-1.

As shown in Table II, additional blocking of IL-1 did not reduce joint inflammation in IL-17-enhanced SCW-induced arthritis even in the absence of TNF-{alpha}. Neutralizing IL-1 did reduce cartilage proteoglycan depletion at day 2 but no longer at day 7, suggesting a role for IL-1 in early IL-17-mediated cartilage degradation. These data indicate that, under these experimental arthritic conditions, IL-17 can act independently of both TNF and IL-1.


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  		Table II. The effect of anti-IL-1 treatment on joint inflammation and cartilage proteoglycan (PG) depletion in IL-17 aggravated SCW-induced arthritis in TNF-deficient micea

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Disclosures
 References
 
In the present study we clearly demonstrated a critical role for TNF-{alpha} in the IL-17-induced joint inflammation and cartilage proteoglycan depletion under naive conditions. In addition, we showed that IL-1 is not required for this IL-17-induced joint pathology. Interestingly, our data revealed that under arthritic conditions this TNF dependency of IL-17 is lost, indicating that IL-17 can act independently of IL-1 and TNF.

Because IL-17 is found in synovium and synovial fluids of RA patients (3, 4, 5, 6, 7), a role for this T cell cytokine is hypothesized in RA pathogenesis. Mice deficient for IL-17 show markedly suppressed collagen-induced arthritis (27) and also fail to develop spontaneous arthritis in the absence of IL-1R antagonist (16). IL-17 involvement has also been demonstrated in the progression of experimental arthritis models. Blocking of IL-17 reduced joint inflammation and bone destruction even after the onset of CIA (12, 31) and has shown great efficacy during reactivation of Ag-induced arthritis (32).

Although IL-17 is not a very potent cytokine in comparison with IL-1 and TNF (1, 23, 45, 46), IL-17 can act in strong synergy with these cytokines (20, 21, 22, 23). This ability, and the fact that IL-17 itself can induce the production of IL-1 and TNF by macrophages (19), raised the question of which role do IL-1 and TNF play in the IL-17-induced joint pathology during experimental arthritis. Previous studies have shown that, although IL-17 increased the IL-1 levels in the synovium, IL-17 overexpression accelerated CIA in an IL-1-independent way. Using IL-1-deficient mice it was also demonstrated that IL-17 enhanced joint inflammation and cartilage damage independently of IL-1 (30, 34). In the present study, the role of TNF in IL-17-induced joint pathology was elucidated using adenoviral IL-17 overexpression in TNF-deficient mice.

In the present study, we demonstrated clear TNF dependency of IL-17-induced pathology under naive conditions. Injection of IL-17 in the knee joint of naive mice results in joint inflammation and cartilage proteoglycan depletion (30, 33). Remarkably, IL-17-induced joint pathology was almost completely abrogated in TNF-deficient mice. No differences in IL-17 production were found, and synovial IL-17 receptor expression in TNF-deficient mice was also normal (data not shown). In addition, no regulation of the TNF receptor by IL-17 was found (data not shown). These results indicate a crucial role for TNF in the initiation of IL-17-induced joint pathology. Our finding of TNF dependency corresponds with previous in vitro studies of macrophages in which anti-TNF treatment completely blocked IL-17-induced matrix metalloproteinase-9 production by macrophages (47). The underlying mechanism of this TNF dependency, however, remains to be elucidated.

Speculating on possible mechanisms for explaining the TNF dependency of IL-17 responses, we consider two major levels at which IL-17 requires TNF for its responses: 1) the transcriptional level; and 2) the posttranscriptional level. Increasing numbers of studies are unraveling the intracellular mechanisms by which IL-17 regulates gene expression. Previously, it was shown that IL-17 activates NF-{kappa}B (12, 13, 14) and requires TNFR-associated factor-6 in intracellular signaling (48). Recent microarray studies also identified C/EBP-{delta} and MAIL/I{kappa}B-{xi} as IL-17-related transcription regulating factors (49). Cross-talk of transcriptional factors, for example NF-{kappa}B and C/EBP{delta}, has been extensively studied (50, 51, 52), explaining the synergistic effects of different cytokines on the induction of gene expression. Our data suggest that IL-17 needs to induce and cooperate with TNF to synergistically up-regulate other proinflammatory genes and subsequently cause the influx of proinflammatory cells and cartilage proteoglycan depletion.

On the level of posttranscriptional regulation, IL-17 is known to stabilize effector mRNA (53, 54). For example, IL-17 markedly enhanced TNF-induced IL-6 and IL-8 secretion through the induction of mRNA stabilization (55, 56), and IL-17 provided a stabilizing signal for TNF-NF{kappa}B-induced I{kappa}B-{zeta} expression (57). Also, TNF mRNA itself is subject to mRNA stabilization, and animal studies have shown that disrupted TNF mRNA destabilization might play a role in the pathogenesis of chronic inflammatory arthritis (58). In the light of these studies, IL-17 might be considered mainly a stabilizer of mRNA that requires TNF-induced NF-{kappa}B activation to augment the production and secretion of proinflammatory cytokines and chemokines.

This hypothesis leads us to explain why IL-1–/– mice did not show reduced joint inflammation after IL-17 overexpression. In contrast to TNF, IL-1 signaling is qualitatively similar to that of IL-17; TNFR-associated factor-6 was first demonstrated in IL-1 signaling (59), NF-{kappa}B, C/EBP{delta}, and I{kappa}B-{xi} are also involved (60, 61), and IL-1, like IL-17, can promote stabilization of unstable mRNA (57). Because IL-1 and IL-17 have many overlapping responses, the lack of one of the two cytokines might be easily bypassed by the presence of the other, as was also shown for the role of IL-1 in cartilage destruction during SCW-induced arthritis (34).

In this study we also showed that, under arthritic conditions, IL-17 clearly lost its TNF dependency. IL-17 was overexpressed in two different acute inflammatory models, the K/BxN serum transfer arthritis model, in which FcR-binding immune complexes play a role (40), and the TLR-MyD88-mediated SCW-induced arthritis (41). Similar results were obtained with IL-17 overexpression during passive immune complex arthritis mediated by lysozyme-antilysozyme complexes (data not shown). These animal models are macrophage-mediated arthritis models with an acute onset and short-lasting local inflammation. In our K/BxN serum transfer arthritis model, arthritis in wrists and ankles was clearly suppressed by genetic background (40, 62). Therefore, this study only focused on the virus-accelerated knee joints. Overexpression of IL-17 in these models aggravated inflammation and joint damage, turning it into a more destructive and chronic arthritis model with chondrocyte death and erosion of cartilage and bone. Besides inflammation and destruction, IL-17 overexpression also induced new bone formation, and the possible role of different growth factors involved in this process needs further investigation. Interestingly, IL-17 could amplify these experimental arthritis models in the absence of TNF, indicating loss of TNF dependency under arthritic conditions. Because we showed TNF independence of IL-17 in two completely different arthritis models, the arthritic stimulus does not seem to be specific for the loss of TNF dependency. Because IL-1, like TNF, acts in synergy with IL-17 in the induction of inflammatory and degradative factors (21, 24, 25, 26), we speculated that the presence of IL-1 during arthritis caused loss of TNF dependency. However, additional blocking of IL-1 under TNF-deficient conditions did not inhibit the IL-17 effects during SCW-induced arthritis. Although we cannot exclude synergy of minor amounts of unblocked IL-1 with IL-17, these data suggest that IL-17 can act independently of both IL-1 and TNF during arthritis. In line with our previous speculations, we suggest that, under arthritis conditions, IL-17 no longer needs TNF for synergistic gene transcription or translation after mRNA stabilization but that the presence of other proinflammatory cytokines and chemokines creates the perfect environment for IL-17 to augment inflammation and joint destruction. The balance of IL-17 and other inflammatory mediators during experimental arthritis might be deciding the TNF dependency of IL-17 in that specific situation.

This is the first report that demonstrates the unique position of TNF in IL-17-induced joint pathology. Despite the strong dependency on TNF under naive conditions, IL-17 acts independently of TNF and IL-1 under arthritic conditions, aggravating joint inflammation and destruction. These data suggest that blocking IL-17 may have additional value in the treatment of destructive arthritis.


   Acknowledgments
 
We thank the Central Animal Laboratory, Radboud University, Nijmegen, The Netherlands for good animal care.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by Dutch Arthritis Association Grant NR 00-1-302, Veni Fellowship Grant 906-02-038 (to E..L.) from the Netherlands Organization for Scientific Research, and a grant from Novartis Pharma AG, Basel, Switzerland. Back

2 Address correspondence and reprint requests to Dr. Marije I. Koenders, Radboud University Nijmegen Medical Center, Experimental Rheumatology and Advanced Therapeutics, 272, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail address: m.koenders{at}reuma.umcn.nl Back

3 Current address: Department of Rheumatology/Immunology, Erasmus Medical Center, Rotterdam, the Netherlands. Back

4 Abbreviations used in this paper: RA, rheumatoid arthritis; CIA, collagen-induced arthritis; SCW, streptococcal cell wall-induced arthritis; WT, wild type; i.a., intraarticular(ly); Ad, adenoviral (vector). Back

Received for publication October 6, 2005. Accepted for publication February 27, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 

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