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Rheumatology Advance Access published online on October 8, 2009
Rheumatology, doi:10.1093/rheumatology/kep293
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© The Author(s) 2009. Published by Oxford University Press on behalf of The British Society for Rheumatology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Investigating the role of the interleukin-23/-17A axis in rheumatoid arthritis

Philippa Hillyer1,*, Maggie J. Larché1,*, Edward P. Bowman2, Terrill K. McClanahan2, Rene de Waal Malefyt2, Lauren P. Schewitz1, Grey Giddins3, Marc Feldmann1, Robert A. Kastelein2 and Fionula M. Brennan1

1Kennedy Institute of Rheumatology, Imperial College, London, UK, 2Schering-Plough Biopharma, Palo Alto, CA, USA and 3Orthopaedic Department, Royal United Hospital, Combe Park, Bath, UK.

Correspondence to: Fionula M. Brennan, Kennedy Institute of Rheumatology, Imperial College London, 1 Aspenlea Road, London W6 8LH, UK. E-mail: f.brennan{at}imperial.ac.uk


  Abstract

Objective. IL-23 is a pro-inflammatory cytokine proposed to be central to the development of autoimmune disease. We investigated whether IL-23, together with the downstream mediator IL-17A, was present and functional in RA in humans.

Methods. RA synovial cells were cultured in the presence or absence of antibodies directed against IL-23p19 or -23R and -17. IL-23, -12, -17, and their receptors, and IL-6, -1β and TNF-{alpha} were measured by ELISA and/or PCR.

Results. Small amounts of cell-associated IL-23 (median 110 pg/ml) were detected in RA synovial cultures, and found to be functional as IL-23R blockade resulting in a significant inhibition of TNF-{alpha} (57%), IL-1β (51%) and IL-6 (30%). However, there was a considerable variability between individual patient samples, and anti-IL-23p19 was found to be considerably less effective. IL-17A protein was detected in ~40% of the supernatants and IL-17A blockade, in IL-17A-producing cultures, resulted in a small but significant inhibition of TNF-{alpha} (38%), IL-1β (23%) and IL-6 (22%). Addition of recombinant IL-23 to cultures had a variable effect on the spontaneous production of endogenous IL-17A with enhancement observed in some but not all cultures, suggesting that either the low levels of endogenous IL-23 are sufficient to support cytokine production and/or that the relevant Th17 cells were not present.

Conclusions. These results suggest that although IL-23 may have pathogenic activity in a proportion of patients with late-stage RA, it is not abundantly produced in this inflammatory tissue, nor does it have a dominant role in all patient tissues analysed.

KEY WORDS: IL-23, IL-17, Rheumatoid arthritis, Anti-IL-23p19, Anti-IL-23R, Synovium, Cytokine

Present address: Maggie Larché, Division of Rheumatology, McMaster University, Hamilton, Ontario Canada.

*Philippa Hillyer and Maggie Larché equally contributed to this work.

Submitted 5 March 2009; revised version accepted 11 August 2009.
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