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Rheumatology Advance Access originally published online on April 8, 2008
Rheumatology 2008 47(6):815-820; doi:10.1093/rheumatology/ken061
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Expression of IL-19 and its receptors in RA: potential role for synovial hyperplasia formation

N. Sakurai, T. Kuroiwa, H. Ikeuchi, N. Hiramatsu, A. Maeshima, Y. Kaneko, K. Hiromura and Y. Nojima

Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Correspondence to: T. Kuroiwa, Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi, Gunma 371-8511, Japan. E-mail: tkuroiwa{at}med.gunma-u.ac.jp


   Abstract

Objective. IL-19 is a novel cytokine of the IL-10 family. In this study, we sought to examine whether IL-19 plays a role in the pathogenesis of RA.

Methods. Expression of IL-19, IL-20 receptor 1 (IL-20R1) and IL-20R2 was examined by RT-PCR and immunohistochemical analysis in rheumatoid synovium. The effects of IL-19 on synovial cells established from rheumatoid synovium (RASCs), with regard to IL-6 production and signal transducers and activators of transcription3 (STAT3) activation, were examined by ELISA and western blot analysis, respectively. The effect of IL-19 on RASC apoptosis was examined by Hoechst staining, flow cytometry analysis of annexin V binding and caspase-3 activity.

Results. IL-19, IL-20R1 and IL-20R2 mRNA were detected by RT-PCR in synovial tissues from RA patients. Immunohistochemical analysis showed IL-19 was predominantly expressed in the hyperplastic lining layers of RA synovial tissues. The majority of IL-19-positive cells were vimentin-positive and CD68-positive synovial cells, serving as markers of fibroblasts and macrophages, respectively. IL-20R1 and IL-20R2 (IL-20Rs) were expressed in both the lining and sublining layers of RA synovium. In RASC, IL-19 was induced by lipopolysaccharide stimulation and constitutive expression of IL-20Rs was observed, suggesting IL-19 has an autocrine action. In terms of this function, IL-19 induced STAT3 activation and increased IL-6 production by RASC above the medium control. Moreover, IL-19 significantly reduced RASC apoptosis induced by serum starvation.

Conclusions. These data suggest that IL-19, produced by synovial cells, promotes joint inflammation in RA by inducing IL-6 production and decreasing synovial cell apoptosis.

KEY WORDS: Rheumatoid arthritis, Interleukin-10 family, Interleukin-19, Synovial hyperplasia, CD68, Vimentin, Synovial cells, STAT3, Interleukin-6, anti-apoptosis

Submitted 4 September 2007; revised version accepted 28 January 2008.
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