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  • IL-32γ and Streptococcus pyogenes cell wall fragments synergise for IL-1-dependent destructive arthritis via upregulation of TLR-2 and NOD2

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Basic and translational research
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IL-32γ and Streptococcus pyogenes cell wall fragments synergise for IL-1-dependent destructive arthritis via upregulation of TLR-2 and NOD2
  1. Bas Heinhuis1,
  2. Marije I Koenders1,
  3. Fons A van de Loo1,
  4. Peter L E M van Lent1,
  5. Soo-Hyun Kim3,
  6. Charles A Dinarello4,
  7. Leo A B Joosten1,2,
  8. Wim B van den Berg1
  1. 1Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  2. 2Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  3. 3Institute of Biomedical Science and Technology, College of Medicine, Konkuk University, Seoul, Korea
  4. 4Division of Infectious Diseases, University of Colorado Denver, Aurora, Colorado, USA
  1. Correspondence to Dr Bas Heinhuis, Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500HB, Nijmegen, The Netherlands; s.heinhuis{at}reuma.umcn.nl

Abstract

Objective To investigate the potential synergism between interleukin (IL) 32γ and Streptococcus pyogenes cell wall (SCW) fragments in the development of destructive arthritis.

Methods An adenoviral vector encoding human IL-32γ (AdIL-32γ) was constructed and validated in HeLa cells. Fibroblast-like synoviocytes (FLS) were transduced with AdIL-32γ and stimulated with Toll-like receptor 2 (TLR-2) and nucleotide oligomerisation domain (NOD) 2 ligands. Expression levels of several proinflammatory cytokines, chemokines, matrix degrading enzymes, TLR-2 and NOD2 were measured by quantitative real-time PCR. Furthermore, IL-6 and CXCL8 protein levels were determined. In-vivo synergy between IL-32γ and SCW was studied by intra-articular injection of AdIL-32γ in C57Bl/6 mice followed by SCW injection. The contribution of endogenous IL-1 was assessed in mice deficient for both IL-1α and IL-1β.

Results IL-32γ synergise with TLR-2/NOD2 ligands to induce proinflammatory cytokines, chemokines and matrix degrading enzymes in AdIL-32γ-transduced FLS. In mice, AdIL-32γ transduction followed by the injection of SCW displayed aggravated joint inflammation and cartilage destruction. However, IL-1-deficient mice were protected against IL-32γ/SCW-induced joint changes, indicating a requirement for IL-1 in downstream events triggered by IL-32γ plus SCW. To elucidate the synergistic mechanism, the authors investigated the expression of two pattern recognition receptors involved in sensing SCW fragments. TLR-2 and NOD2 receptor expression was enhanced by IL-32γ and Pam3Cys/muramyl dipeptide stimulation in FLS.

Conclusions Here the authors show that IL-32γ aggravates SCW-induced arthritis by the upregulation of TLR-2/NOD2 expression and promotes severe joint erosion in an IL-1-dependent fashion. Targeting of IL-32γ may provide a novel therapy to prevent destructive arthritis.

https://doi.org/10.1136/ard.2009.127399

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    Footnotes

    • LABJ and WBvdB authors shared senior authorship

    • Competing interests None.

    • Funding BH was supported by a research grant from the Dutch Arthritis Association (06-1-301). CAD and SHK were supported by a grant from the National Institutes of Health AI-15614.

    • Ethics approval Animal studies were approved by the institutional ethics committee.

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