Background and Objectives Rheumatoid arthritis (RA) is a chronic destructive autoimmune disease with periods of exacerbation and remission. An attractive treatment would provide a disease-regulated therapy that offers flexible drug delivery. Therefore, we expressed the anti-inflammatory interleukin-10 (IL-10) gene under the control of an inflammation-dependent promoter in a mouse model of RA.
Materials and Methods Proximal promoters of S100a8, Cxcl1, Mmp13, Saa3, IL-1b, and TSG6 were selected from endogenous genes differentially regulated in the inflamed synovium of arthritic mice. Mice were injected intra-articularly in kneejoints with lentiviral vectors expressing a luciferase reporter or the therapeutic protein IL-10 under control of selected promoter. After 4 days, arthritis was induced by intra-articular injection of streptococcal cell walls. At different timepoints after arthritis induction, in-vivo bioluminescent imaging was performed or knee joints were dissected for histological and RNA analysis.
Results The disease-regulated promoters showed different activation profiles during the course of the disease, subsequently the Saa3 and MMP13 promoter were selected for further research, because of differences in activation at day 1. Overexpression of IL-10 resulted in less synovitis and cartilage proteoglycan (PG) depletion and in upregulation of IL-1Ra and SOCS3 gene expression. IL-1Ra counteracts the detrimental effects of IL-1 on cartilage damage and SOCS3 inhibits the JAK/STAT pathway and subsequent inflammation; this can explain the diminished synovitis and PG depletion. Probably because IL-10 is expressed at day 1 of arthritis without any treatment, major therapeutic differences between the MMP13 and SAA3 promoter were not evident in this study.
Conclusion We can conclude that local inflammation-dependent IL-10 gene therapy suppresses experimental arthritis and is a promising strategy in the development of novel treatments for RA.