Skip Navigation


Rheumatology Advance Access originally published online on May 11, 2006
Rheumatology 2006 45(12):1485-1489; doi:10.1093/rheumatology/kel154
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
45/12/1485    most recent
kel154v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Peake, N. J.
Right arrow Articles by Foster, H. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Peake, N. J.
Right arrow Articles by Foster, H. E.
Related Collections
Right arrow Pregnancy and Rheumatic Diseases
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Interleukin-6 signalling in juvenile idiopathic arthritis is limited by proteolytically cleaved soluble interleukin-6 receptor

N. J. Peake, K. Khawaja1, A. Myers, M. A. Nowell2, S. A. Jones2, A. D. Rowan, T. E. Cawston and H. E. Foster

Musculoskeletal Research Group, School of Clinical Medical Sciences, University of Newcastle-upon-Tyne, UK, 1Department of Paediatrics, Newcastle Hospitals NHS Trust, Newcastle-upon-Tyne, UK and 2Medical Biochemistry & Immunology, School of Medicine, University of Cardiff, Wales, UK.

Correspondence to: Dr H. E. Foster, Musculoskeletal Research Group, Medical School Cookson Building, University of Newcastle-upon-Tyne, NE2 4HH, UK. E-mail: h.e.foster{at}ncl.ac.uk


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Ojectives. Interleukin-6 (IL-6) exerts multiple effects on chondrocytes and fibroblasts within the joint and is associated with disease activity in juvenile idiopathic arthritis (JIA). Although these cells express the ubiquitous signalling receptor for all IL-6-related cytokines, gp130, they do not express a cognate IL-6 receptor. Consequently, IL-6 responses within these cells occur via IL-6 trans-signalling relying on the presence of a soluble receptor (sIL-6R). Levels of sIL-6R in vivo are governed by either proteolytic cleavage (PC) of cognate receptor or by differential sIL-6R mRNA splicing (DS). The aim of this study was to evaluate the contribution of both isoforms to clinical parameters associated with IL-6 signalling in JIA.

Methods. IL-6, sIL-6R and DS-sIL-6R were measured by ELISA in serum and synovial fluid (SF) samples from 86 JIA patients. These data were related to indicators of inflammation-erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) and compared between patients stratified by subtype, age and disease duration.

Results. SF IL-6 significantly correlated with general indicators of activity (ESR and CRP) and SF PC-sIL-6R to a lesser degree with CRP. When the IL-6:sIL-6R ratio was calculated as an indicator of the potential for IL-6 signalling within the joint, 33% of SF samples showed a ratio >1 indicating saturation of sIL-6R by IL-6. Mean DS-sIL-6R levels were 0.71 ng/ml, whereas PC-sIL-6R levels constituted the majority of sIL-6R at 20.89 ng/ml.

Conclusions. IL-6 trans-signalling within the joints of JIA patients is predominantly governed by the presence of PC-sIL-6R, and the data provided suggest that synovial levels of IL-6 and sIL-6R would be sufficient to drive IL-6 responses in chondrocytes and synovial fibroblasts.

KEY WORDS: JIA, Interleukin-6, Soluble receptor, Differential splicing, Proteolytic cleavage


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Interleukin-6 (IL-6) is a pleiotropic cytokine that coordinates both pro- and anti-inflammatory activities during disease [1–4]. Differential control of these properties is closely related to the ability of IL-6 to suppress innate immune responses and its capacity to promote acquired immunity [5]. Within the context of arthritis, IL-6 can affect expression of inflammatory mediators, leucocyte trafficking, synovitis, cartilage degradation and joint erosion. Indeed an active role for IL-6 in joint pathology is strongly endorsed in experimental models of arthritis, where IL-6-deficient mice remain resistant to disease progression [6–9].

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases of unknown aetiology with an age of onset under 16 yrs. In the current International League Against Rheumatism (ILAR) classification, JIA is grouped into eight subtypes based primarily on the clinical features exhibited by patients within the first 6 months [10]. JIA is not a benign disease and up to one-third of patients experience active disease into adulthood, which can impact on quality of life and functional ability, leading to eventual joint failure requiring replacement surgery [11].

IL-6 is associated with disease activity in JIA. It is found at high levels in the synovial fluid (SF), and is associated with indicators of inflammatory activity such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). IL-6 genotype has recently been associated with the degree of pain during disease [12–16]. In addition to classical activation of IL-6 response through binding a membrane-bound IL-6 receptor (IL-6R), IL-6 has the capacity to elicit responses in cell types that would not inherently respond via the formation of an agonistic complex with soluble IL-6R (sIL-6R). A process known as trans-signalling [17], this has the potential to govern key cellular mediators of joint catabolism, chondrocytes and fibroblasts [4, 18, 19]. Regulation of these IL-6 responses is transmitted via the ubiquitously expressed signal transducing receptor for all IL-6-related cytokines, gp130, and the control of these processes in JIA may have considerable importance in disease progression.

IL-6 and sIL-6R in combination have been shown to synergize with IL-1 to stimulate proteinase production in chondrocytes [3], which has been implicated in the breakdown of joint components. sIL-6R is produced by two distinct mechanisms: proteolytic cleavage (PC) from membranes of cell types that express cognate IL-6R; and differential splicing (DS) of IL-6R mRNA. PC-sIL-6R is thought to be responsible for the majority of soluble receptor in serum [1], which can be induced by CRP, chemokines, complement components and lipid mediators [20], and there is evidence that this cleavage is mediated by metalloproteinases [21, 22]. The aim of this study was to measure these isoforms of sIL-6R during active JIA, and to relate these data to the level of IL-6 in synovial fluids and serum, and to clinical indicators of disease activity.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients and samples
This study was performed on 186 SF samples and 152 serum samples, including 133 paired samples, from 86 JIA patients diagnosed according to the ILAR criteria. Parental or patient consent was obtained, and sample collection was performed under appropriate ethical guidelines. The subtypes studied were persistent oligoarthritis (n= 52), extended oligoarthritis (n= 18) and polyarthritis (n= 16, of whom 3 were RF+). Active joint count (AJC), ESR and CRP levels were obtained, where available, from routine monitoring of disease activity, for 94, 75 and 66 SF samples, and 89, 66 and 61 serum samples, respectively. Clinical data were stratified according to age of onset, disease duration and age at sample time. Medication regimen at the time of sampling was also recorded (corticosteroid treatment, non-steroidal anti-inflammatory drugs, disease modifying anti-rheumatic drugs). We were able to compare data sets from a wide range of patient ages and disease durations. The mean age of onset was 7 yrs, and mean disease duration 7 yrs; thus the age of the first sample collected varied considerably, from 2 to 48 yrs, with a mean of 14 yrs.

Determination of IL-6 and sIL-6R
IL-6 and sIL-6R enzyme-linked immunosorbent assay (ELISA) kits were obtained from R&D Systems (Oxford, catalogue numbers #DY206 and DY227, respectively). These kits measure both free and complexed IL-6/sIL-6R, and were used according to the manufacturer's instructions. The linear range was 4.7–300 pg/ml for IL-6 and 15.6–1000 pg/ml for sIL-6R. Samples were diluted to a minimum of 1:5 in sample buffer, and results below the limit of detection were allocated a value of 0.05 ng/ml for statistical purposes. DS-sIL-6R was detected using a modification of the sIL-6R kit above. The capture antibody was replaced by a specific anti-DS-sIL-6R antibody generated by Dr Sankichi Horiuchi (Department of Microbiology, Tokyo Medical and Dental University, Japan). This antibody, mAb2F3, is raised against a COOH-terminal peptide unique to DS-sIL-6R (GSRRRGSCGL [23]), and was used at 2 µg/ml. The linear range was 31.25–2000 pg/ml of protein standard generated from a baculovirus-expressed DS-sIL-6R from insect cell culture [24].

Statistical analysis
Spearman's correlation analysis of the measurements was used to assess the relationship between clinical and laboratory criteria and all samples with available data were utilized in each of these analyses. For group comparisons, the data were log-transformed to achieve normal distribution and analysed by t-test or ANOVA, and, where multiple samples were available from a patient, the mean level was used, with time between samples ranging up to 6 yrs. Paired t-test was used when assessing paired SF and serum levels on the log-transformed data.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgements
 References
 
Measurement of IL-6 and sIL-6R in JIA samples
IL-6 was detected in 174/183 (95%) of SF and 39/151 (26%) of sera tested, with mean (±S.D.) levels of 8.38± 11.71 ng/ml and 0.35± 1.74 ng/ml, respectively (P< 0.0001). Conversely, sIL-6R, detected in all SF and serum assayed, was higher in serum compared with SF with levels of 38.09± 20.62 ng/ml and 21.38± 15.36 ng/ml, respectively. This difference was significant (P< 0.0001), though not exclusive—11/131 (8.2%) of paired samples showed higher levels in SF. It was also observed that serum and SF levels correlated (Fig. 1A).


Figure 1
View larger version (17K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		FIG. 1. The relationship between serum and SF levels of sIL-6R (A), DS-sIL-6R (B) and PC-sIL-6R (C). Significant correlations were observed. Serum levels of DS- and PC-sIL-6R also showed a significant correlation (D). Regression lines are indicated by dashed line.

 
Molecular weights of 25 kDa and 65 kDa were used for IL-6 and sIL-6R, respectively [25, 26], in order to calculate molar concentrations and thus the IL-6:sIL-6R ratio. This ratio in SF ranged 0.003–26.8, with a mean of 1.54. Notably, 61/183 samples (33%) with available data had a ratio >1. The sIL-6R level in these samples, therefore, appeared to be saturated by the level of IL-6 with regard to chondrocyte and fibroblast response. In contrast, in serum the ratio ranged 0.001–4.2 with a mean of 0.05, and only 2/151 samples (1.3%) had a ratio >1.

Measurement of sIL-6R isoforms in JIA samples
The SF DS-sIL-6R levels ranged from 0.001 to 5.84 ng/ml, with a mean (±S.D.) of 0.71± 0.81 ng/ml. The serum DS-sIL-6R levels ranged from 0.006 to 3.369 ng/ml, with a mean (±S.D.) of 0.69± 0.55 ng/ml (n= 136). Thus the levels were similar in SF and serum. PC-sIL-6R was calculated by subtracting DS-sIL-6R level from total sIL-6R, and the levels ranged from 0.07 to 94.21 ng/ml in SF, with a mean (±S.D.) of 20.89± 15.71 ng/ml. In serum, the PC-sIL-6R levels ranged from 6.69 to 142.96 ng/ml, with a mean (±S.D.) of 38.14± 20.76 ng/ml. Thus, PC-sIL-6R constituted the majority of sIL-6R in both serum and SF. We noted that SF and serum values of DS-sIL-6R (Fig. 1B) and PC-sIL-6R (Fig. 1C) correlated significantly. We also observed that serum DS- and PC-sIL-6R showed a statistically significant correlation (Fig. 1D), while no such relationship was found in SF.

Assocation of IL-6, sIL-6R and DS-/PC-sIL-6R with clinical data in JIA patients
We tested the measurements for association with CRP, ESR and AJC, in order to assess a link to inflammatory activity. SF IL-6 correlated significantly with ESR (R= 0.51, P< 0.0001) and CRP (R= 0.56, P< 0.0001). Further, SF PC-sIL-6R showed a significant correlation with CRP (R= 0.25, P< 0.05).

To investigate the relationship of IL-6 and the receptor isoforms with clinical phenotype, the patients were clustered by JIA subtype, and the measurements compared between groups. Neither IL-6 nor sIL-6R levels were significantly different between JIA subtypes. SF IL-6 concentrations tended to be higher in polyarticular JIA compared with oligoarticular persistent or extended populations (12.05 ng/ml, compared with 6.98 and 6.91 ng/ml, respectively). However, this was not statistically significant. Similarly, the IL-6:sIL-6R ratio was not different between subtypes (Fig. 2A), nor were DS-sIL-6R and PC-sIL-6R concentrations (Fig. 2B and C, respectively) or relative DS:PC levels.


Figure 2
View larger version (21K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		FIG. 2. The IL-6:sIL-6R ratio (A), DS-sIL-6R level (B) and PC-sIL-6R levels (C) in the JIA subtypes studied, and comparison of SF DS-sIL-6R level between samples taken during concurrent steroid therapy compared with samples taken without such treatment (D). The Il-6:sIL-6R ratio was >1 in many SF samples, indicating saturation of IL-6 response by local chondrocytes and fibroblasts, though no difference was seen between JIA subtypes. DS-sIL-6R levels were similar in serum and SF, compared with PC-sIL-6R levels, which were significantly higher in serum. However, levels of DS- or PC-sIL-6R were not significantly different between the subtypes in either SF or serum. A significant difference was observed in SF DS-sIL-6R level between samples taken during concurrent steroid therapy compared with samples taken without such treatment (D). Lines indicate mean± 95% CI.

 
No differences were observed between any of the measurements between patients grouped by disease duration or age, indicating that IL-6 and sIL-6R are present from early disease and throughout the disease course. Finally, we analysed the association of the measurements with medication regimen. DS-sIL-6R was significantly higher in the SF of patients with concurrent steroid therapy (Fig. 2D). None of the measurements was significantly different when compared between samples taken with or without methotrexate or non-steroidal anti-inflammatory drugs.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgements
 References
 
IL-6 has previously been shown to be associated with disease activity in JIA [14–16], most notably in systemic JIA where it has been proposed as a key mediator of the disease process, and anti-IL-6 therapy has recently been shown to be effective in treating this subtype [12, 27]. In this study, we found a statistically significant correlation between IL-6 and both ESR and CRP. A potent immunomodulatory cytokine, IL-6 has also been shown to act on cell types within the joint, such as chondrocytes and fibroblasts, in the presence of sIL-6R promoting activity associated with joint breakdown such as synovial proliferation and release of proteinases [3, 4].

No data are currently available on the isoforms of soluble receptor in JIA. We found high levels of sIL-6R in both the serum and SF of JIA patients, and the serum levels were higher—an observation supported by previous studies [28, 29]. IL-6:sIL-6R is a physiologically significant ratio, as IL-6 and sIL-6R constantly associate and dissociate prior to complexing with gp130. By measuring this ratio, we can therefore estimate the capacity for local IL-6 signalling requiring both molecules. We have demonstrated that this ratio indicates a saturation of IL-6 trans-signalling in a third of SF samples assayed.

SF PC-sIL-6R levels were found to show a significant correlation with CRP. CRP promotes proteolytic shedding of the membrane-bound IL-6 receptor [20], and it is also noteworthy that proteolytic shedding is mediated by metalloproteinases. The joint environment has been shown to be highly proteolytic in JIA, with up-regulation of metalloproteinases associated with the degree of inflammation, which may contribute to local proteolytic cleavage of IL-6R from infiltrating cell types that do express the receptor [22, 30, 31]. An increase in local proteolytic shedding may also explain why SF DS- and PC-sIL-6R did not show a significant correlation as seen in serum, whereas in SF this was not the case. However, the differences between significant and non-significant results observed are small, and further work is therefore necessary to substantiate this fact.

Hepatocytes are a major source of serum sIL-6R [29], and it was therefore of interest to study the influence of medications on sIL-6R level. SF levels of DS-sIL-6R were higher in patients with concurrent steroid therapy. Up-regulation of IL-6R by glucocorticoids has been noted in several cell types including epithelial cells and hepatocytes [32–34], and cytokines such as oncostatin M and IL-1 appear to stimulate differential splicing [32, 35]. Our results indicate that glucocorticoids may also stimulate local production of the differentially spliced isoform, though we did not find a similarly significant relationship in the serum (P= 0.08). It is noteworthy, however, that no difference in physiological function has been attributed to the two isoforms of sIL-6R [36]. Further work would be interesting to examine the interaction of steroid therapy with local soluble receptor production given its importance in mediating IL-6 effects in chondrocytes and fibroblasts.

In conclusion, we have provided important and novel data on the levels of sIL-6R during active JIA, and demonstrated the presence of two isoforms during disease. These data illustrate that sIL-6R is an important consideration in the events leading to IL-6-mediated effects within the joint.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
We thank the Faculty of Medical Sciences, University of Newcastle-upon-Tyne, for the award of a research studentship to N.J.P, the Arthritis Research Campaign for the award of a senior clinical lectureship to H.E.F, and the Dunhill Medical Trust and Anne Coleman Arthritis Fund for essential support for this work. Finally, we thank Dr Sankichi Horiuchi and Prof. Naoki Yamamoto for the DS-sIL-6R mAb 2F3.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Jones SA, Horiuchi S, Topley N, Yamamoto N, Fuller GM. (2001) The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J 15:43–58.[Abstract/Free Full Text]
  2. Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW. (1994) Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 83:113–8.[Abstract/Free Full Text]
  3. Rowan AD, Koshy PJ, Shingleton WD, et al. (2001) Synergistic effects of glycoprotein 130 binding cytokines in combination with interleukin-1 on cartilage collagen breakdown. Arthritis Rheum 44:1620–32.[CrossRef][ISI][Medline]
  4. Mihara M, Moriya Y, Kishimoto T, Ohsugi Y. (1995) Interleukin-6 (IL-6) induces the proliferation of synovial fibroblastic cells in the presence of soluble IL-6 receptor. Br J Rheumatol 34:321–5.[Abstract/Free Full Text]
  5. Jones SA. (2005) Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol 175:3463–8.[Abstract/Free Full Text]
  6. Alonzi T, Fattori E, Lazzaro D, et al. (1998) Interleukin 6 is required for the development of collagen-induced arthritis. J Exp Med 187:461–8.[Abstract/Free Full Text]
  7. Boe A, Baiocchi M, Carbonatto M, Papoian R, Serlupi-Crescenzi O. (1999) Interleukin 6 knock-out mice are resistant to antigen-induced experimental arthritis. Cytokine 11:1057–64.[CrossRef][ISI][Medline]
  8. Sasai M, Saeki Y, Ohshima S, et al. (1999) Delayed onset and reduced severity of collagen-induced arthritis in interleukin-6-deficient mice. Arthritis Rheum 42:1635–43.[CrossRef][ISI][Medline]
  9. Ohshima S, Saeki Y, Mima T, et al. (1998) Interleukin 6 plays a key role in the development of antigen-induced arthritis. Proc Natl Acad Sci USA 95:8222–6.[Abstract/Free Full Text]
  10. Petty RE, Southwood TR, Manners P, et al. (2004) International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 31:390–2.[ISI][Medline]
  11. Foster HE, Marshall N, Myers A, Dunkley P, Griffiths ID. (2003) Outcome in adults with juvenile idiopathic arthritis: a quality of life study. Arthritis Rheum 48:767–75.[CrossRef][ISI][Medline]
  12. De Benedetti F, Martini A. Is systemic juvenile rheumatoid arthritis an interleukin 6 mediated disease? J Rheumatol (1998) 25:203–7.[ISI][Medline]
  13. Oen K, Malleson PN, Cabral DA, et al. (2005) Cytokine genotypes correlate with pain and radiologically defined joint damage in patients with juvenile rheumatoid arthritis. Rheumatology 44:1115–21.[Abstract/Free Full Text]
  14. De Benedetti F, Robbioni P, Massa M, Viola S, Albani S, Martini A. (1992) Serum interleukin-6 levels and joint involvement in polyarticular and pauciarticular juvenile chronic arthritis. Clin Exp Rheumatol 10:493–8.[ISI][Medline]
  15. Madson KL, Moore TL, Lawrence JM 3rd, Osborn TG. (1994) Cytokine levels in serum and synovial fluid of patients with juvenile rheumatoid arthritis. J Rheumatol 21:2359–63.[ISI][Medline]
  16. Kutukculer N, Caglayan S, Aydogdu F. (1998) Study of pro-inflammatory (TNF-alpha, IL-1alpha, IL-6) and T-cell-derived (IL-2, IL-4) cytokines in plasma and synovial fluid of patients with juvenile chronic arthritis: correlations with clinical and laboratory parameters. Clin Rheumatol 17:288–92.[CrossRef][ISI][Medline]
  17. Kallen KJ. (2002) The role of transsignalling via the agonistic soluble IL-6 receptor in human diseases. Biochim Biophys Acta 1592:323–43.[Medline]
  18. Silacci P, Dayer JM, Desgeorges A, Peter R, Manueddu C, Guerne PA. (1998) Interleukin (IL)-6 and its soluble receptor induce TIMP-1 expression in synoviocytes and chondrocytes, and block IL-1-induced collagenolytic activity. J Biol Chem 273:13625–9.[Abstract/Free Full Text]
  19. Harigai M, Hara M, Kitani A, et al. (1991) Interleukin 1 and tumor necrosis factor-alpha synergistically increase the production of interleukin 6 in human synovial fibroblast. J Clin Lab Immunol 34:107–13.[Medline]
  20. Jones SA, Novick D, Horiuchi S, Yamamoto N, Szalai AJ, Fuller GM. (1999) C-reactive protein: a physiological activator of interleukin 6 receptor shedding. J Exp Med 189:599–604.[Abstract/Free Full Text]
  21. Matthews V, Schuster B, Schutze S, et al. (2003) Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE). J Biol Chem 278:38829–39.[Abstract/Free Full Text]
  22. Mullberg J, Durie FH, Otten-Evans C, et al. (1995) A metalloprotease inhibitor blocks shedding of the IL-6 receptor and the p60 TNF receptor. J Immunol 155:5198–205.[Abstract]
  23. Horiuchi S, Ampofo W, Koyanagi Y, et al. (1998) High-level production of alternatively spliced soluble interleukin-6 receptor in serum of patients with adult T-cell leukaemia/HTLV-I-associated myelopathy. Immunology 95:360–9.[CrossRef][ISI][Medline]
  24. Jones SA, Horiuchi S, Novick D, Yamamoto N, Fuller GM. (1998) Shedding of the soluble IL-6 receptor is triggered by Ca2+ mobilization, while basal release is predominantly the product of differential mRNA splicing in THP-1 cells. Eur J Immunol 28:3514–22.[CrossRef][ISI][Medline]
  25. Helle M, Boeije L, de Groot E, de Vos A, Aarden L. (1991) Sensitive ELISA for interleukin-6. Detection of IL-6 in biological fluids: synovial fluids and sera. J Immunol Methods 138:47–56.[CrossRef][ISI][Medline]
  26. Muller-Newen G, Kohne C, Keul R, et al. (1996) Purification and characterization of the soluble interleukin-6 receptor from human plasma and identification of an isoform generated through alternative splicing. Eur J Biochem 236:837–42.[ISI][Medline]
  27. Woo P, Wilkinson N, Prieur AM, et al. (2005) Open label phase II trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement. Arthritis Res Ther 7:R1281–8.[CrossRef][ISI][Medline]
  28. De Benedetti F, Massa M, Pignatti P, Albani S, Novick D, Martini A. (1994) Serum soluble interleukin 6 (IL-6) receptor and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis. J Clin Invest 93:2114–9.[ISI][Medline]
  29. Desgeorges A, Gabay C, Silacci P, et al. (1997) Concentrations and origins of soluble interleukin 6 receptor-alpha in serum and synovial fluid. J Rheumatol 24:1510–6.[ISI][Medline]
  30. Peake NJ, Khawaja K, Myers A, et al. (2005) Levels of matrix metalloproteinase (MMP)-1 in paired sera and synovial fluids of juvenile idiopathic arthritis patients: relationship to inflammatory activity, MMP-3 and tissue inhibitor of metalloproteinases-1 in a longitudinal study. Rheumatology 44:1383–9.[Abstract/Free Full Text]
  31. Peake NJ, Foster HE, Khawaja K, Cawston TE, Rowan AD. (2005) Assessment of the clinical significance of gelatinase activity in juvenile idiopathic arthritis patients using quantitative protein substrate zymography. Ann Rheum Dis 65:501–7.
  32. Geisterfer M, Richards CD, Gauldie J. (1995) Cytokines oncostatin M and interleukin 1 regulate the expression of the IL-6 receptor (gp80, gp130). Cytokine 7:503–9.[CrossRef][ISI][Medline]
  33. Nesbitt JE and Fuller GM. (1992) Differential regulation of interleukin-6 receptor and gp130 gene expression in rat hepatocytes. Mol Biol Cell 3:103–12.[Abstract]
  34. Snyers L, De Wit L, Content J. (1990) Glucocorticoid up-regulation of high-affinity interleukin 6 receptors on human epithelial cells. Proc Natl Acad Sci USA 87:2838–42.[Abstract/Free Full Text]
  35. Cichy J, Rose-John S, Potempa J, Pryjma J, Travis J. (1997) Oncostatin M stimulates the expression and release of the IL-6 receptor in human hepatoma HepG2 cells. J Immunol 159:5648–53.[Abstract]
  36. McLoughlin RM, Hurst SM, Nowell MA, et al. (2004) Differential regulation of neutrophil-activating chemokines by IL-6 and its soluble receptor isoforms. J Immunol 172:5676–83.[Abstract/Free Full Text]
Submitted 17 August 2005; revised version accepted 7 April 2006.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
45/12/1485    most recent
kel154v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Peake, N. J.
Right arrow Articles by Foster, H. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Peake, N. J.
Right arrow Articles by Foster, H. E.
Related Collections
Right arrow Pregnancy and Rheumatic Diseases
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?