Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Synergy Between IL-32 and Streptococcus Pyogenes Cell Wall Fragments Results in Destructive Arthritis Which Is IL-1-Dependent
Heinhuis1, Bas, Koenders1, Marije I., van de Loo1, Fons A., van Lent1, Peter L.E.M., Kim2, Soo-Hyun, Dinarello2, Charles A., Joosten1, Leo A.B.
IL-32 might play an important role in the pathogenesis of RA by inducing cytokines, and chemokines. IL-32 is highly expressed in RA synovial tissue and strongly correlates with synovial inflammation, TNFa and IL-1 expression. IL-32 alone is not that potent, but it appears to enhance sensitivity of synovial cells to proinflammatory stimuli. Here, we investigated potential synergistic effects of IL-32g with Streptococcus pyogenes cell wall (SCW) fragments, which contain predominantly TLR2/NOD2 ligands, in human fibroblast like synoviocytes (FLS). In addition, we explored the synergistic arthritogenicity of IL-32g and SCW fragments in wildtype and IL-1 deficient mice.
FLS from 4 arthritis patients were isolated and transduced with an adenoviral vector encoding for IL-32g (AdIL-32g) followed by SCW stimulation. To investigate in vivo synergy, we injected AdIL-32g virus together with SCW fragments intraarticularly into knee joints of wildtype and IL-1 deficient mice.
In human FLS synergistic upregulation of the proinflammatory cytokines IL-1b, IL-6, and TNFa was found and similar observation was made for the chemokines CCL2, CCL20, and CXCL8. Of great importance, we also identified synergistic upregulation of matrix degrading enzymes, including MMP1 and MMP3, linking the IL-32 synergy to erosive processes. Part of the synergy may be related to the marked increase of the pattern recognition receptors TLR2 and NOD2. In wildtype mice we observed a prolonged and severe arthritis injected with AdIL-32g/SCW compared to AdControl/SCW. Furthermore, histological analysis showed apart from enhanced numbers of inflammatory cells, severe cartilage proteoglycan depletion, and irreversible chondrocyte death in mice exposed to IL-32g and TLR2/NOD2 ligands. Remarkably, IL-1 deficient mice injected with AdIL-32g/SCW were completely protected against the destructive arthritis observed in wildtype mice.
The observed synergistic effect between IL-32g and TLR2/NOD2 ligands identifies an important amplifying pathway in the development of destructive arthritis which is IL-1 dependent. Both IL-32g and TLR2/NOD2 are potential novel therapeutic targets in RA.
To cite this abstract, please use the following information:
Heinhuis, Bas, Koenders, Marije I., van de Loo, Fons A., van Lent, Peter L.E.M., Kim, Soo-Hyun, Dinarello, Charles A., et al; Synergy Between IL-32 and Streptococcus Pyogenes Cell Wall Fragments Results in Destructive Arthritis Which Is IL-1-Dependent [abstract]. Arthritis Rheum 2009;60 Suppl 10 :2043