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Rheumatology Advance Access published online on May 11, 2006
Rheumatology, doi:10.1093/rheumatology/kel154
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© 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
Received August 17, 2005
Accepted April 7, 2006

Concise Report

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

N. J. Peake 1, K. Khawaja 2, A. Myers 1, M. A. Nowell 3, S. A. Jones 3, A. D. Rowan 1, T. E. Cawston 1, and H. E. Foster 1 *

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

* To whom correspondence should be addressed.
H. E. Foster, E-mail: h.e.foster{at}ncl.ac.uk


  Abstract

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.

Keywords: JIA; Interleukin-6; Soluble receptor; Differential splicing; Proteolytic cleavage.
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