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IL-17A- versus IL-17F-induced intracellular signal transduction pathways and modulation by IL-17RA and IL-17RC RNA interference in rheumatoid synoviocytes
  1. Arnaud Hot,
  2. Saloua Zrioual,
  3. Myew-Ling Toh,
  4. Vanina Lenief,
  5. Pierre Miossec
  1. Department of Immunology and Rheumatology, University of Lyon, Lyon, France
  1. Correspondence to Professor Pierre Miossec, Clinical Immunology Unit, Department of Immunology and Rheumatology, Hospital Edouard Herriot, 69437 Lyon Cedex 03, France; pierre.miossec{at}univ-lyon1.fr

Abstract

Objective The aim of this study was to compare the effects of interleukin (IL)-17A and IL-17F on gene expression and signalling in human rheumatoid arthritis (RA) synoviocytes.

Methods IL-17A- and IL-17F-induced mRNA expression was analysed using Affymetrix microarrays. IL-6 and IL-8 secretion was evaluated by ELISA. Inhibition of two receptors (IL-17RA and IL-17RC) was achieved by small interfering RNA (saran). The effects on mitogen-activated protein kinase (MAPK), activator protein 1 (AP-1) and nuclear factor κB (NF-κB) expression and activation were evaluated by western blotting, qRT-PCR and DNA binding assay.

Results IL-17A and IL-17F induced a molecular pattern characterised by 27 inflammation-related genes for IL-17F and 165 for IL-17A. Virtually all IL-17A and IL-17F inducible genes were dependent on NF-κB activation, whereas a small number were modulated by p38. IL-17A induced activation of all three MAPKs (ERK, p38 and JNK) and downstream transcription factors AP-1 and p65 NF-κB. IL-17F was less potent but induced activation of p50 NF-κB. IL-17A was more potent at inducing IL-6 secretion than IL-17F, which was inactive alone. IL-17A and, to a lesser extent, IL-17F induced TRAF6 but not MyD88. Inhibition of either IL-17RA or IL-17RC expression via siRNA led to near complete abrogation of IL-6 expression mediated by IL-17A and the combination of IL-17F and tumour necrosis factor α.

Conclusion Like IL-17A, IL-17F regulates proinflammatory gene expression by a very similar but not identical signalling pathway involving IL-17RA and IL-17RC.

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Footnotes

  • Funding This work was supported in part by grants from the Hospices Civils de Lyon and the Region Rhône-Alpes. AH is supported by the Société Nationale de Médecine Interne. SZ was supported by a scholarship from the Region Rhône-Alpes. M-LT was supported by a fellowship from the Region Rhône-Alpes.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the ethics committee of the Hospitals of Lyon.

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

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