Article Text

other Versions

PDF
Extended report
Role of IL-17 in the Th1 systemic defects in rheumatoid arthritis through selective IL-12Rβ2 inhibition
  1. Myew-Ling Toh,
  2. Masanori Kawashima,
  3. Arnaud Hot,
  4. Philippe Miossec,
  5. Pierre Miossec
  1. Department of Immunology and Rheumatology, Immunogenomics and Inflammation Research Unit EA 4130, University of Lyon, Edouard Herriot Hospital, Lyon, France
  1. Correspondence to Professor Pierre Miossec, Clinical Immunology Unit, Department of Immunology and Rheumatology, Edouard Herriot Hospital, 5 Place d’Arsonval, 69437 Lyon Cedex 03, France; miossec{at}univ-lyon1.fr

Abstract

Background Patients with rheumatoid arthritis (RA) have a systemic Th1 defect associated with inflammation.

Objective To examine the hypothesis that interleukin 17 (IL-17) contributes to this defect.

Methods IL-17 effects on Th1 markers were examined on T-bet and interferon γ (IFNγ) expression in peripheral blood mononuclear cells (PBMCs) from patients with RA or healthy controls (HC). Receptor specificities were determined by analysis of the Th1-specific IL-12 receptor β2 (IL-12Rβ2), Th17-specific IL-23R and the common IL-12Rβ1 chain expression. Effects of IL-17 or IFNγ on IL-6, IL-1, IL-8, matrix metalloproteinase-8 (MMP-8) were measured by real-time RT-PCR in RA synovial cells.

Results RA PBMCs were less responsive to IL-12-induced IFNγ than HC PBMCs. IL-12 hyporesponsiveness was increased by IL-17 treatment associated with a selective reduction in IL-12Rβ2, but not IL-23R, IL-12Rβ1 or T-bet, which was reversed with IL-17R inhibition. IL-17 inhibited IL-12Rβ2 expression in developing Th1 cells. In RA synovial cells, IL-17 induced IL-6, IL-1, IL-8 and MMP-8, whereas IFNγ had minimal or inhibitory effects.

Conclusion In RA, IL-12 hyporesponsiveness is associated with IL-17R-mediated downregulation of IL-12Rβ2 expression. IL-17 may reinforce Th17 lineage commitment and proinflammatory and destructive effects through Th1 inhibition and positive feedback effects in RA synovial cells. Anti-inflammatory effects of IL-17/IL-17R antagonism may include the restoration of protective Th1 responses.

Statistics from Altmetric.com

Footnotes

  • Funding This work was supported in part by grants from the Hospices Civils of Lyon and the Region Rhône-Alpes. M-LT and MK were supported by a fellowship from the Region Rhône-Alpes. AH was supported by a grant from the Société Française de Médecine Interne.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Hospital of Lyon.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent Obtained.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.