Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production
Version of Record online: 28 DEC 2010
Copyright © 2011 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 63, Issue 1, pages 73–83, January 2011
How to Cite
van Hamburg, J. P., Asmawidjaja, P. S., Davelaar, N., Mus, A. M. C., Colin, E. M., Hazes, J. M. W., Dolhain, R. J. E. M. and Lubberts, E. (2011), Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production. Arthritis & Rheumatism, 63: 73–83. doi: 10.1002/art.30093
- Issue online: 28 DEC 2010
- Version of Record online: 28 DEC 2010
- Accepted manuscript online: 15 OCT 2010 01:46PM EST
- Manuscript Accepted: 7 OCT 2010
- Manuscript Received: 13 MAY 2010
- Dutch Arthritis Association
Both Th1 cells and Th17 cells have been recognized in rheumatoid arthritis (RA); however, it remains unclear whether Th1 cells and/or Th17 cells are involved in driving disease chronicity and destructiveness. The aim of this study was to identify and characterize the functional role of Th17 cells in early RA.
Flow cytometry analysis was performed on peripheral blood mononuclear cells (PBMCs) from treatment-naive patients with early RA and age-matched healthy volunteers. PBMCs from these patients, naive T cells, and primary CCR6− Th1 cells and CCR6+ Th17 cells were sorted and cultured in the absence or presence of synovial fibroblasts from patients with early RA (RASFs), and cytokine expression and gene transcription were analyzed. In addition, tumor necrosis factor α (TNFα)– and interleukin-17A (IL-17A)–blocking experiments were performed.
In the PBMCs of treatment-naive patients with early RA, an increased fraction of IL-17A–and TNFα–producing CCR6+ Th17 cells was observed. When cocultured with RASFs, these primary Th17 cells were potent inducers of IL-6 and IL-8 and the tissue-destructive enzymes matrix metalloproteinase 1 (MMP-1) and MMP-3, whereas primary Th1 cells or naive T cells were not. Importantly, specific up-regulation of IL-17A but not TNFα or interferon-γ was observed in RASF/Th17 cell cocultures. In addition to TNFα blocking, IL-17A neutralization was required to further down-regulate Th17 activity in RASF/Th17 cell cocultures.
Th17 cells, but not Th1 cells, cooperated with RASFs in a proinflammatory feedback loop, revealing a potential mechanism by which human Th17 cells drive chronic destructive disease in patients with RA. Furthermore, the neutralization of IL-17A activity is essential in current anti-TNF therapies to suppress Th17 cell activity in patients with early RA and potentially other Th17 cell–mediated disorders.