Local interleukin-12 gene transfer promotes conversion of an acute to a chronic destructive murine streptococcal cell wall arthritis

Objective

Interleukin-12 is a pleiotropic cytokine that is produced by mononuclear phagocytes, dendritic cells and B cells, and it promotes the growth of activated T cells and NK cells. IL-12 selectively generates the development of naïve T cells into Th1 cells. IL-12 is effectively produced by macrophages upon stimulation with LPS, several bacteria and intracellular parasites. The goal of the present was to determine whether local overexpression of IL-12 converts an acute joint inflammation to a chronic destructive arthritis.

Method

SCW arthritis was induced in IL-12 deficient mice to examine the IL-12 dependency. C57Black/6 mice were injected intra-articularly with either saline, 10⁷ pfu control vector (Ad5del70-3) or IL-12 vector (AdmIL-12.1) into the right knee joint one day before the mice were injected intra-articularly with 25 μg SCW fragments. Thereafter, joint swelling, chondrocyte proteoglycan (PG) synthesis and joint destruction were examined. In addition MMP activity was visualized by VDIPEN staining. Arthritis was exacerbated by intravenous injection of 100 μg SCW fragments.

Results

IL-12-deficient mice showed reduced joint swelling after injection of SCW fragments. High levels of IL-12 (up to 20 ng/ml at day 1) could be detected after application of AdIL-12 vector. After 14 days still expression of IL-12 (1 ng/ml) was found locally without significant inflammation. Local expression of IL-12 reveals to aggravate SCW arthritis as determined by enhanced joint swelling and inhibition of chondrocyte PG synthesis. Histology taken at day 21 showed a chronic inflammatory process in the AdIL-12 transfected knee joints. Enhanced cartilage PG depletion and cartilage destruction was noted in the AdIL-12 group, whereas this was not seen in the Ad5del70-5 group. In line with these findings, metalloproteinase activity, visualized by VDIPEN expression in the cartilage layers, was only found in AdIL-12 group. In addition, systemic challenge of arthritis was only possible in the AdmIL-12 group, indicating a T cell mediated process.

Conclusion

These results indicate that local expression of IL-12 can promote conversion of an acute to a chronic destructive arthritic process.