%0 Journal Article %A Bas Heinhuis %A Marije I Koenders %A Fons A van de Loo %A Peter L E M van Lent %A Soo-Hyun Kim %A Charles A Dinarello %A Leo A B Joosten %A Wim B van den Berg %T IL-32γ and Streptococcus pyogenes cell wall fragments synergise for IL-1-dependent destructive arthritis via upregulation of TLR-2 and NOD2 %D 2010 %R 10.1136/ard.2009.127399 %J Annals of the Rheumatic Diseases %P 1866-1872 %V 69 %N 10 %X 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. %U https://ard.bmj.com/content/annrheumdis/69/10/1866.full.pdf