Adenoviral vector-mediated overexpression of IL-4 in the knee joint of mice with collagen-induced arthritis prevents cartilage destruction

Rheumatoid arthritis is a chronic inflammatory joint disease, leading to ca rtilage and bone destruction. In this study, we investigated the effects of local IL-4 application, introduced by a recombinant human type 5 adenoviru s vector, in the knee joint of mice with collagen-induced arthritis. One in traarticular injection with an IL-4-expressing virus caused overexpression of IL-4 in the mouse knee joint. Enhanced onset and aggravation of the syno vial inflammation were found in the IL-4 group. How ever, despite ongoing i nflammation, histologic analysis showed impressive prevention of chondrocyt e death and cartilage erosion. In line with this, chondrocyte proteoglycan synthesis was enhanced in the articular cartilage, This was quantified with ex vivo S-35-sulfate incorporation in patellar cartilage and confirmed by autoradiography on whole knee joint sections. Reduction of cartilage erosio n was further substantiated by lack of expression of the stromelysin-depend ent cartilage proteoglycan breakdown neoepitope VDIPEN in the Ad5E1 mIL-4-t reated knee joint. Reduced metalloproteinase activity was also supported by markedly diminished mRNA expression of stromelysin-3 in the synovial tissu e. Histologic analysis revealed marked reduction of polymorphonuclear cells in the synovial joint space in the IL-4-treated joints. This was confirmed by immunolocalization studies on knee joint sections using NIMP-R14 staini ng and diminished mRNA expression of macrophage-inflammatory protein-2 in t he synovium tissue, mRNA levels of TNF-alpha and IL-1 beta were suppressed as well, and IL-1 beta and nitric oxide production by arthritic synovial ti ssue were strongly reduced. Our data show an impressive cartilage-protectiv e effect of local IL-4 and underline the feasibility of local gene therapy with this cytokine in arthritis.