|
|
|
|
|
|
|
||
BRIEF DEFINITIVE REPORT |
CORRESPONDENCE Eddie Chung Yern Wang: WangEC{at}cf.ac.uk
 Top ABSTRACT RESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting
DR3 (TRAMP, LARD, Apo3, Wsl1, and TNFRSF25) is a member of the TNFRSF and shows closest homology to TNFR1 (6). Like TNFR1, DR3 contains four extracellular cysteine-rich repeats and is capable of signaling both apoptosis via caspase 8 activation and cell survival via the activation of NF
To address this, we have generated mice lacking the DR3 gene (DR3ko) on a C57BL/6 background (10) and used a salient model of experimental arthritis to elucidate functional aspects of DR3 activity. Antigen-induced arthritis (AIA) is a local model of disease which displays many pathological features of RA including cellular infiltration, synovial hyperplasia, pannus formation, cartilage depletion, and bone destruction (21). We show that DR3 is essential for the development of adverse joint pathology in AIA and that anti-TL1A treatment can protect from the systemic model of disease, collagen-induced arthritis (CIA). These results imply an important in vivo function for DR3 in the pathogenesis of inflammatory arthritis and provide proof of principle that countering this pathway may represent a novel therapy for RA. 
1% of the global population (1). RA is characterized by infiltration of synovial joints by immune cells, principally macrophages, T cells, plasma cells, and hyperplasia of the synovial lining. This eventually results in the destructive phase of disease causing damage to cartilage and bone. It is widely accepted that cytokines and their receptors play a central role in the pathogenesis of RA, thus TNF
, IL-1, and IL-6 have been identified as key mediators of the disease (2–4). The role played by members of the TNF receptor superfamily (TNFRSF) in pathological bone resorption has also become widely accepted, with RANK and RANKL acting as crucial factors in differentiation of osteoclasts (5), the primary cell type involved in bone degradation. 
B (7–9). The biological function of DR3 is an area of growing interest. In the immune system, DR3 has been shown to affect negative selection during thymocyte development (10) and can modulate T cell (11–13) and NKT cell function (14). It has also been associated with inflammatory diseases such as irritable bowel disease (15, 16) and atherosclerosis (17). Interestingly, DR3, along with its only known ligand, TNF-like protein 1A (TL1A) (18), has been linked with RA. Duplication of the DR3 gene is more prevalent in RA patients compared with controls (19), whereas TL1A+ mononuclear phagocytes have been identified in rheumatoid synovium and soluble TL1A has been detected in synovial fluid of patients (20). However, functional analysis of the in vivo role of the DR3–TL1A pathway in RA has not yet been reported.
RESULTS AND DISCUSSION
Top
ABSTRACT
RESULTS AND DISCUSSION
MATERIALS AND METHODS
REFERENCES
DR3ko mice show reduced inflammatory response to AIA compared with DR3wt controls
To investigate the in vivo role of DR3 in inflammatory arthritis, we induced AIA in DR3ko mice and DR3wt controls. All mice developed an inflammatory reaction in response to intraarticular injection of methylated BSA, with both DR3ko and DR3wt mice exhibiting a similar pattern of joint swelling over a 21-d time course. Comparable knee joint swelling measurements were noted in DR3ko and DR3wt mice at the peak of response, 1 d after mBSA injection. Thereafter, swelling resolved in both but faster in the absence of DR3 (Fig. 1 A).
|
, IL-1β, and IL-6 reach a peak and destructive pathology first becomes detectable (3 d after induction) and when there is maximal evidence of structural damage within the joint (21 d after induction) (21). The severity of arthritis (arthritis index [AI]) was quantified in hematoxylin and eosin (H&E)–stained sections by grading parameters as described in Materials and methods. On day 3 after arthritis induction, DR3wt (Fig. 1 B) and DR3ko mice (Fig. 1 C) did not differ histopathologically. By day 21, DR3wt mice had developed arthritis characterized by extensive cellular infiltration, synovial hyperplasia, formation of a thick pannus, and bone erosions (Fig. 1 D). In contrast, DR3ko mice displayed mild pathological features of arthritis, showing general absence of synovial hyperplasia, lack of pannus formation, and no evidence of bone erosion (Fig. 1 E). Indeed, all scoring parameters were either absent or significantly milder in DR3ko compared with DR3wt mice (Fig. 1 F). This translated into a significant reduction in the AI (Fig. 1 G). As a second outcome measure of structural damage to the joint, we assessed proteoglycan depletion from articular cartilage on the femoral head using Safranin O/Fast Green staining 21 d after arthritis induction. In DR3wt mice, cartilage was severely depleted, as illustrated by lack of red Safranin O staining resulting in an obvious tidemark (Fig. 1 H). DR3ko mice did not display much cartilage depletion (Fig. 1 I), retaining similar levels of Safranin O staining as nonarthritic control left knees (not depicted). Collectively, this data indicate that there is considerable protection against degenerative AIA disease pathology in DR3ko mice.
TL1A exacerbates disease in a DR3-dependent fashion
To confirm that resistance to AIA was DR3 specific, TL1A was injected with mBSA on day 0 of the AIA model at escalating quantities up to 100 ng. DR3het mice were chosen as they showed intermediate AI scores compared with DR3wt mice (Figs. 1 G and 2 A). Consequently, exacerbation or amelioration of disease after TL1A injection could be quantified, irrespective of the inherent variability in the model. Coadministration of TL1A resulted in significant dose-dependent exacerbation of disease in DR3het mice (Fig. 2 A). This was strikingly illustrated by the effect on size of bone erosions and severity of bone destruction, which increased in a dose-dependent fashion after TL1A injection (Fig. 2, B and C). In contrast, TL1A had no significant effect on arthritis progression in DR3ko mice over the concentration range studied (Fig. 2 D). Representative images of DR3ko mice receiving 1 and 100 ng TL1A show the continued absence of bone erosions (Fig. 2, E and F). TL1A therefore exacerbates AIA and, in particular, adverse bone pathology in a DR3-dependent manner.
|
|
TL1A promotes osteoclastogenesis in vitro in a DR3-dependent fashion
We therefore tested the possibility that TL1A could directly promote differentiation of osteoclasts. To achieve this, we used an in vitro system of osteoclastogenesis from adherent BM-derived cells (BMC). BM macrophages (BMM) from DR3wt mice were confirmed to express DR3 (Fig. 4 A). BMC from DR3wt and DR3ko mice did not differ in their ability to generate osteoclasts in the presence of soluble RANK-L and M-CSF as measured by the formation of multinucleated TRAP+ cells (Fig. 4 B). However, TL1A addition significantly enhanced development of osteoclasts from DR3wt but not DR3ko BMC (Fig. 4, B–D). TL1A in the absence of RANK-L and M-CSF could not generate osteoclasts (Fig. 4 E). The functional capacity of in vitro–generated osteoclasts to destroy bone was visualized by toluidine blue staining of pits in the ivory discs (Fig. 4 F). This data indicates that TL1A is not necessary for osteoclastogenesis per se, but promotes it in the presence of RANK-L and M-CSF and in a DR3-dependent fashion. In support of our murine data and highlighting the significance of these results for humans, TL1A significantly promoted osteoclastogenesis from monocytes derived from human peripheral blood (Fig. 4 G).
|
|
This is the first paper reporting that signaling through DR3 on myeloid cells promotes osteoclastogenesis, although it is clear from our data that it is not a prerequisite for, nor can it induce, this differentiation in the absence of RANK-L and M-CSF. In this respect, it mirrors functions that have been reported for TNF (23). However, a function independent of TNF is suggested by a recent paper showing that macrophages produce TL1A independent of TNF activity (20). TL1A expression, including release of active soluble forms of the protein, can be induced on human monocytes by Fc
R stimulation through soluble (24) and insoluble immune complexes purified from RA synovial fluid (20). The majority of stromal macrophages in RA synovial tissue express TL1A, and in vitro stimulation of monocytes with PEG precipitates from RA samples results in production of nanogram quantities of soluble TL1A (20). This suggests very high levels in localized RA joint akin to the levels we used to exacerbate AIA (Fig. 2 A). The implication is that in inflammatory arthritis, myeloid cells may exhibit a positive feedback loop whereby TL1A is triggered through ICs and can drive differentiation of bone-destroying cells if the right cytokine milieu is provided. Intriguingly, TL1A also has varied effects on human osteoblast cell lines in vitro, inhibiting differentiation and promoting quiescence at low densities but inducing death at high densities (25). We therefore propose that the DR3–TL1A pathway may act as a switch that is capable of directly activating osteoclast but also inhibiting osteoblast differentiation and, in so doing, disregulate the homeostatic balance of degradation and formation in normal bone into the detrimental situation observed in destructive bone pathologies such as RA. Although our in vitro data supports this proposal, some caution is necessary in interpreting the contribution of direct TL1A-driven osteoclastogenesis to arthritic bone damage in vivo, as inflammation and bone erosion cannot be dissociated in AIA or CIA. The possibility remains that the resistance of DR3ko mice to bone erosion is secondary to DR3–TL1A-dependent control of other parts of the inflammatory process.
In this respect, our data also show that cartilage depletion is significantly reduced in DR3ko mice (Fig. 1). Cartilage depletion is attributed to the effects of matrix metalloproteinases (MMPs), levels of which are raised in RA joint. In vitro experiments on human cell lines have shown that DR3 activation can induce the production of MMP-1, -9, and -13 in THP-1s (17). These MMPs have all been associated with RA joint pathology (26). In addition, it is also established that TL1A plays an important role in T cell function. TL1A has been shown to costimulate IL-2 responsiveness (11) and synergize with the TCR and IL-12/IL-18 pathways to induce IFN release (15, 27, 28). TL1A also amplifies cytokine release by NKT cells (14) and T cells (13) and regulates the development of proinflammatory Th17 cells (12, 16), which are reported to aid osteoclastogenesis in autoimmune arthritis (29). The action of TL1A on T cells may also be regulated by differential expression of splice variants of DR3 (27). The exact role of TL1A and DR3 on lymphocytes in inflammatory arthritis remains to be elucidated, but it is interesting to note that we find normal anti-mBSA Ab levels in serum, unchanged T cell proliferation to mBSA in draining lymph nodes of DR3ko mice after AIA induction, and normal in vitro generation of Th17 cells from DR3ko splenocytes (unpublished data).
In summary, we have induced inflammatory arthritis in DR3ko mice and found that they exhibit strong resistance to the adverse pathology observed in AIA. We show DR3-dependent TL1A-driven exacerbation of bone damage in vivo and promotion of osteoclastogenesis in vitro. We also show that anti-TL1A therapy ameliorates disease. Our data suggest that the DR3–TL1A pathway is an important component of inflammatory responses in joint disease and, as such, identifies a potential therapeutic target for treatment of diseases like RA but with potential impact in other diseases involving disrupted bone physiology.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Induction of murine AIA.
AIA was induced as previously described (30). In brief, mice were s.c. immunized on two occasions, 1 wk apart, with 1 mg/ml mBSA with an equal volume of CFA. An additional i.p. injection of 100 µl of heat-inactivated Bordetella pertussis toxin was administered with the first immunization. AIA was induced in the hind right knee joint via an intraarticular injection of 10 mg/ml mBSA (6 µl), administered 21 d after the initial immunization. To assess the effect of TL1A or anti-TL1A administration, AIA was induced via mBSA injection in conjunction with 1, 10, or 100 ng of soluble TL1A (R&D Systems) or 100 ng of anti-TL1A mAb.
Generation of a rat anti–mouse TL1A monoclonal antibody.
Rats were immunized with a soluble recombinant TL1A protein consisting of a human IgG1 Fc domain, with an additional hinge-like region at the C terminus, linked to the extracellular domain of mouse TL1A (T77-L252). The protein was produced in Chinese hamster ovary cells and was purified by immunoaffinity chromatography using an anti–human Fc mAb. Anti-TL1A mAb was generated by standard hybridoma technology and hybridoma supernatants were screened for binding to recombinant soluble and membrane-expressed TL1A. To generate cells expressing membrane-anchored TL1A, PCR fragments encoding the entire coding sequence of mouse TL1A were cloned into the mammalian expression vectors pEF1/V5-His A and pcDNA3.1 (Invitrogen), and plasmids were then transfected into J558L or 293T cells. Stable J558L cell lines expressing membrane-anchored TL1A were selected in Geneticin (400 µg/ml)-containing media. Splenic cDNA or IMAGE clone 30740802 was used as a template for PCR reactions to generate TL1A-encoding DNA fragments. Further selection of neutralizing anti-TL1A mAbs was based on the ability to block binding of soluble recombinant TL1A-Fc to anti-CD3/CD28–stimulated T cells.
Anti-TL1A therapy in CIA.
CIA was induced as previously described (31). In brief, 2 mg/ml of chicken type II collagen (CII; Sigma-Aldrich) was emulsified with an equal volume of complete Freund's adjuvant and 100 µl of collagen/adjuvant mixture injected intradermally into several sites near the base of the tail of 7-wk-old male DBA/1J mice. A second identical booster was administered to each mouse 21 d after the first injection. The day of the first immunization was designated as day 0. Mice were randomly assigned to one of three treatment groups on day 20. Animals received nine daily 100-µl injections containing either 2.5 mg/kg of anti-TL1A or LEAF purified control rat IgG2a (Cambridge Biosciences) dissolved in sterile PBS or PBS alone administered by the i.p. route from day 20. Thereafter, arthritis incidence and severity was assessed daily until termination on day 28 when the disease severity limits were attained in IgG2a and PBS controls. The incidence of CIA was assessed as the percentage of mice developing arthritis among all mice. The severity of arthritis in each paw (paw score) was evaluated by using an established in-house scoring system: 0, normal; 1, mild but definite swelling in the ankle or wrist joint or redness and swelling limited to individual digits regardless of the number of digits affected; 2, moderate swelling of ankle or wrist; 3, severe redness and swelling of the ankle or wrist and proximal phalangeal joints; and 4, maximally inflamed limb with involvement of multiple joints, no ankylosis.
Assessment of arthritis.
Joint swelling was assessed on days 1, 2, 3, 5, 7, 14, and 21 after arthritis induction by measuring the difference between hind right (AIA) and hind left (control) knee joint diameters using an analogue micrometer. Animals were killed on day 3 or 21 for assessment of inflammatory and pathological changes within the joint. Histological assessment was performed as previously described (30). All joints were fixed in neutral buffered formal saline and decalcified with 10% formic acid for 2 wk at 4°C before embedding in paraffin wax. Serial sections of 7-µm thickness were taken and stained routinely with H&E for analysis. Two blinded independent observers scored the sections for cellular infiltration (0–5), cellular exudate (0–3), synovial hyperplasia (0–3), and bone erosion (0–3), with 0 representing a normal joint. The sum of all parameters gave the AI. Sections were additionally stained with Safranin O and Fast Green to assess cartilage depletion.
RT-PCR.
BMM were generated as previously described (32). RNA was extracted from BMM cultures using RNeasy (QIAGEN) after manufacturer's instructions, whereas cDNA was generated and RT-PCR performed according to standard Invitrogen protocols. PCR primers were as follows: β-actin, forward 5'-CGGCCAGGTCATCACTATTG-3' and reverse 5'-CTCAGTAACCCGCCTAG-3' giving a 410-bp product; and DR3, forward 5'-CTAAGGCTTGCACTGCTGTCT-3' and reverse 5'-GAGCATCTCATACTGCTGGTC-3' giving a 457-bp product. The PCR consisted of 33 cycles with a 59°C annealing temperature.
TRAP staining for osteoclasts.
For TRAP staining, joints were decalcified in EDTA (7%), rehydrated, and incubated with TRAP staining solution containing 0.1 M acetate buffer, 0.5 M sodium tartrate, 10 mg/ml naphthol AS-MX phosphate, 100 µl Triton X-100, and 0.3 mg/ml Fast Red Violet LB salt for 3 h at 37°C. Sections were then counterstained with hematoxylin before mounting in DPX. Images were captured using a digital camera (N457; Olympus), and TRAP-positive cells were analyzed using Photoshop CS3. 5 (Adobe). Randomly chosen selected areas were used for analysis.
Immunohistochemistry for F4/80 expression.
F4/80 expression was detected using an anti–rat HRP-DAB staining kit (R&D Systems) according to the manufacturer's instructions. In brief, sections were rehydrated and endogenous peroxidase activity was blocked. Antigen unmasking was achieved by incubating the sections in 0.1% prewarmed Trypsin/EDTA in PBS for 30 min at 37°C. After blocking steps, sections were incubated overnight with 4 µg/ml of rat anti-F4/80 antibody (Invitrogen) or isotype control diluted in PBS followed by secondary antibody as per the manufacturer's instructions. Positively labeled cells were visualized using a streptavidin-HRP conjugate and DAB chromogen. Sections were counterstained with hematoxylin, dehydrated, and mounted in DPX. Images were captured using a digital camera (N457), and F4/80 positive cells were analyzed using Photoshop. Randomly selected areas were used for analysis.
In vitro osteoclastogenesis assays.
BMC were removed from femurs of DR3wt and DR3ko mice by centrifugation after removal of the proximal end. BMC were resuspended in -MEM supplemented with 10% FCS, 2 mM L-glutamine, and antibiotics (MEM-10) and 5 x 105 cells added to ivory discs. After 2 h at 37°C, nonadherent cells were removed by transfer of ivory discs to new wells with fresh media supplemented with 50 ng/ml RANKL and 25 ng/ml M-CSF with or without 10 ng/ml TL1A. All media were replenished after 3 d. TRAP staining was performed according to the manufacturer's instructions (Sigma-Aldrich) after 7 d. Six fields of view on each disc were counted for TRAP-positive multinucleated cells. For human osteoclastogenesis assays, peripheral blood mononuclear cells were used as a source for adherent cells and cultures were maintained for 21 d before TRAP staining.
Statistical analysis.
Readouts could not be assumed to be normally distributed as they were histological scores or percentages. Therefore, nonparametric Mann-Whitney U tests were used for statistical analysis. One-way unpaired and two-way ANOVAs were used when testing the influence of third parameters such as time or dose. Analyses were performed on GraphPad Prizm v4. P-values of 
0.05 were considered significant and values of 0.01 were considered highly significant.
|
Acknowledgments |
|---|
The authors have no conflicting financial interests.
Submitted: 6 November 2007
Accepted: 2 September 2008
© 2008 Bull et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
|
REFERENCES |
|---|
|
TopABSTRACTRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
1 Feldmann, M., F.M. Brennan, and R.N. Maini. 1996. Rheumatoid arthritis. Cell. 85:307–310.[CrossRef][Medline]
2 Williams, R.O., M. Feldmann, and R.N. Maini. 1992. Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc. Natl. Acad. Sci. USA. 89:9784–9788.
3 Abramson, S.B., and A. Amin. 2002. Blocking the effects of IL-1 in rheumatoid arthritis protects bone and cartilage. Rheumatology (Oxford). 41:972–980.[CrossRef][Medline]
4 Boe, A., M. Baiocchi, M. Carbonatto, R. Papoian, and O. Serlupi-Crescenzi. 1999. Interleukin 6 knock-out mice are resistant to antigen-induced experimental arthritis. Cytokine. 11:1057–1064.[CrossRef][Medline]
5 Asagiri, M., and H. Takayanagi. 2007. The molecular understanding of osteoclast differentiation. Bone. 40:251–264.[CrossRef][Medline]
6 Kitson, J., T. Raven, Y.P. Jiang, D.V. Goeddel, K.M. Giles, K.T. Pun, C.J. Grinham, R. Brown, and S.N. Farrow. 1996. A death-domain-containing receptor that mediates apoptosis. Nature. 384:372–375.[CrossRef][Medline]
7 Bodmer, J.L., K. Burns, P. Schneider, K. Hofmann, V. Steiner, M. Thome, T. Bornand, M. Hahne, M. Schroter, K. Becker, et al. 1997. TRAMP, a novel apoptosis-mediating receptor with sequence homology to tumor necrosis factor receptor 1 and Fas(Apo-1/CD95). Immunity. 6:79–88.[CrossRef][Medline]
8 Screaton, G.R., X.N. Xu, A.L. Olsen, A.E. Cowper, R. Tan, A.J. McMichael, and J.I. Bell. 1997. LARD: a new lymphoid-specific death domain containing receptor regulated by alternative pre-mRNA splicing. Proc. Natl. Acad. Sci. USA. 94:4615–4619.
9 Marsters, S.A., J.P. Sheridan, C.J. Donahue, R.M. Pitti, C.L. Gray, A.D. Goddard, K.D. Bauer, and A. Ashkenazi. 1996. Apo-3, a new member of the tumor necrosis factor receptor family, contains a death domain and activates apoptosis and NF-kappa B. Curr. Biol. 6:1669–1676.[CrossRef][Medline]
10 Wang, E.C., A. Thern, A. Denzel, J. Kitson, S.N. Farrow, and M.J. Owen. 2001. DR3 regulates negative selection during thymocyte development. Mol. Cell. Biol. 21:3451–3461.
11 Migone, T.S., J. Zhang, X. Luo, L. Zhuang, C. Chen, B. Hu, J.S. Hong, J.W. Perry, S.F. Chen, J.X. Zhou, et al. 2002. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity. 16:479–492.[CrossRef][Medline]
12 Pappu, B.P., A. Borodovsky, T.S. Zheng, X. Yang, P. Wu, X. Dong, S. Weng, B. Browning, M.L. Scott, L. Ma, et al. 2008. TL1A-DR3 interaction regulates Th17 cell function and Th17–mediated autoimmune disease. J. Exp. Med. 205:1049–1062.
13 Meylan, F., T.S. Davidson, E. Kahle, M. Kinder, K. Acharya, D. Jankovic, V. Bundoc, M. Hodges, E.M. Shevach, A. Keane-Myers, et al. 2008. The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases. Immunity. 29:79–89.[CrossRef][Medline]
14 Fang, L., B. Adkins, V. Deyev, and E.R. Podack. 2008. Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation. J. Exp. Med. 205:1037–1048.
15 Bamias, G., C. Martin III, M. Marini, S. Hoang, M. Mishina, W.G. Ross, M.A. Sachedina, C.M. Friel, J. Mize, S.J. Bickston, et al. 2003. Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease. J. Immunol. 171:4868–4874.
16 Takedatsu, H., K.S. Michelsen, B. Wei, C.J. Landers, L.S. Thomas, D. Dhall, J. Braun, and S.R. Targan. 2008. TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-Helper 1 and T-Helper 17 activation. Gastroenterology. 135:552–567.[CrossRef][Medline]
17 Kang, Y.J., W.J. Kim, H.U. Bae, D.I. Kim, Y.B. Park, J.E. Park, B.S. Kwon, and W.H. Lee. 2005. Involvement of TL1A and DR3 in induction of pro-inflammatory cytokines and matrix metalloproteinase-9 in atherogenesis. Cytokine. 29:229–235.[CrossRef][Medline]
18 Bossen, C., K. Ingold, A. Tardivel, J.L. Bodmer, O. Gaide, S. Hertig, C. Ambrose, J. Tschopp, and P. Schneider. 2006. Interactions of tumor necrosis factor (TNF) and TNF receptor family members in the mouse and human. J. Biol. Chem. 281:13964–13971.
19 Osawa, K., N. Takami, K. Shiozawa, A. Hashiramoto, and S. Shiozawa. 2004. Death receptor 3 (DR3) gene duplication in a chromosome region 1p36.3: gene duplication is more prevalent in rheumatoid arthritis. Genes Immun. 5:439–443.[CrossRef][Medline]
20 Cassatella, M.A., G.P. da Silva, I. Tinazzi, F. Facchetti, P. Scapini, F. Calzetti, N. Tamassia, P. Wei, B. Nardelli, V. Roschke, et al. 2007. Soluble TNF-like cytokine (TL1A) production by immune complexes stimulated monocytes in rheumatoid arthritis. J. Immunol. 178:7325–7333.
21 Simon, J., R. Surber, G. Kleinstauber, P.K. Petrow, S. Henzgen, R.W. Kinne, and R. Brauer. 2001. Systemic macrophage activation in locally-induced experimental arthritis. J. Autoimmun. 17:127–136.[CrossRef][Medline]
22 Al-Lamki, R.S., J. Wang, A.M. Tolkovsky, J.A. Bradley, J.L. Griffin, S. Thiru, E.C. Wang, E. Bolton, W. Min, P. Moore, et al. 2008. TL1A both promotes and protects from renal inflammation and injury. J. Am. Soc. Nephrol. 19:953–960.
23 Lam, J., S. Takeshita, J.E. Barker, O. Kanagawa, F.P. Ross, and S.L. Teitelbaum. 2000. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J. Clin. Invest. 106:1481–1488.[Medline]
24 Prehn, J.L., L.S. Thomas, C.J. Landers, Q.T. Yu, K.S. Michelsen, and S.R. Targan. 2007. The T cell costimulator TL1A is induced by FcgammaR signaling in human monocytes and dendritic cells. J. Immunol. 178:4033–4038.
25 Borysenko, C.W., V. Garcia-Palacios, R.D. Griswold, Y. Li, A.K. Iyer, B.B. Yaroslavskiy, A.C. Sharrow, and H.C. Blair. 2006. Death receptor-3 mediates apoptosis in human osteoblasts under narrowly regulated conditions. J. Cell. Physiol. 209:1021–1028.[CrossRef][Medline]
26 Burrage, P.S., K.S. Mix, and C.E. Brinckerhoff. 2006. Matrix metalloproteinases: role in arthritis. Front. Biosci. 11:529–543.[Medline]
27 Bamias, G., M. Mishina, M. Nyce, W.G. Ross, G. Kollias, J. Rivera-Nieves, T.T. Pizarro, and F. Cominelli. 2006. Role of TL1A and its receptor DR3 in two models of chronic murine ileitis. Proc. Natl. Acad. Sci. USA. 103:8441–8446.
28 Papadakis, K.A., D. Zhu, J.L. Prehn, C. Landers, A. Avanesyan, G. Lafkas, and S.R. Targan. 2005. Dominant role for TL1A/DR3 pathway in IL-12 plus IL-18-induced IFN-gamma production by peripheral blood and mucosal CCR9+ T lymphocytes. J. Immunol. 174:4985–4990.
29 Sato, K., A. Suematsu, K. Okamoto, A. Yamaguchi, Y. Morishita, Y. Kadono, S. Tanaka, T. Kodama, S. Akira, Y. Iwakura, et al. 2006. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J. Exp. Med. 203:2673–2682.
30 Williams, A.S., M. Mizuno, P.J. Richards, D.S. Holt, and B.P. Morgan. 2004. Deletion of the gene encoding CD59a in mice increases disease severity in a murine model of rheumatoid arthritis. Arthritis Rheum. 50:3035–3044.[CrossRef][Medline]
31 Campbell, I.K., J.A. Hamilton, and I.P. Wicks. 2000. Collagen-induced arthritis in C57BL/6 (H-2b) mice: new insights into an important disease model of rheumatoid arthritis. Eur. J. Immunol. 30:1568–1575.[CrossRef][Medline]
32 Calder, C.J., L.B. Nicholson, and A.D. Dick. 2005. A selective role for the TNF p55 receptor in autocrine signaling following IFN-gamma stimulation in experimental autoimmune uveoretinitis. J. Immunol. 175:6286–6293.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
Related In this Issue article
This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
| |
) or DR3ko (
) mice. Two-way analysis of variance (ANOVA) shows significance at P < 0.02 (*). One representative experiment of three is shown. (B–E) Representative images from DR3wt (B) and DR3ko (C) mice, 3 d after arthritis induction, and DR3wt (D) and DR3ko (E) mice, 21 d after arthritis induction. Bars, 200 µm. Inflammatory tissue (black arrowheads) and erosions (blue arrowheads) are shown. (F) Breakdown of each component of the AI. *, P < 0.05; **, P < 0.01. (G) AI scores from DR3wt and DR3ko mice. **, P < 0.01. Lines mark means of graphed points. (H and I) Representative images of collagen around knee joints from DR3wt (H) and DR3ko (I) mice. Sections were stained with Safranin O/Fast Green to visualize collagen in red. Tidemark of cartilage depletion (arrows) is shown. Bars, 50 µm. (J) Estimated cartilage depletion from DR3wt and DR3ko mice. *, P < 0.05. Each point in the summary graphs represents a single 6 DR3wt (
) or without (
) exogenous TL1A added. **, P = 0.0013. One representative experiment of two is shown.