Adenoviral Transfer of Cyclin-Dependent Kinase Inhibitor Genes Suppresses Collagen-Induced Arthritis in Mice

• Published in: The Journal of immunology (1950) 2000-12, Vol.165 (12), p.7246-7252
• Main Authors: Nasu, Kimio, Kohsaka, Hitoshi, Nonomura, Yoshinori, Terada, Yoshio, Ito, Hiroshi, Hirokawa, Katsuiku, Miyasaka, Nobuyuki
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; adenovirus; Animals; Arthritis, Experimental - enzymology; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; Arthritis, Experimental - prevention & control; Carrier Proteins - biosynthesis; Carrier Proteins - genetics; Carrier Proteins - therapeutic use; Cell Division - genetics; Cell Division - immunology; Cells, Cultured; Cip1 protein; Collagen - immunology; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21; cyclin-dependent kinase inhibitors; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclins - biosynthesis; Cyclins - genetics; Cyclins - therapeutic use; Down-Regulation - genetics; Down-Regulation - immunology; Enzyme Inhibitors - administration & dosage; Gene Transfer Techniques; Genetic Vectors - administration & dosage; Growth Inhibitors - genetics; Growth Inhibitors - physiology; Humans; Immunosuppressive Agents - administration & dosage; Injections, Intra-Articular; INK4a protein; Interleukin-1 - antagonists & inhibitors; Interleukin-1 - biosynthesis; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - biosynthesis; Male; Mice; Mice, Inbred DBA; Synovial Membrane - pathology; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.165.12.7246

In rheumatoid synovial tissues, synovial fibroblasts are activated by proinflammatory cytokines and proliferate to develop hyperplastic pannus tissues, which irreversibly damage the affected joints. We recently reported that the cyclin-dependent kinase inhibitors p16(INK4a) and p21(Cip1) are not expressed in vivo in rheumatoid synovial fibroblasts, but are readily inducible in vitro. This observation was followed by the successful treatment of rat adjuvant arthritis by local p16(INK4a) gene transfer, showing that the inhibition of the cell cycle of the synovial cells ameliorates the arthritis. In this study, we show that another animal model of rheumatoid arthritis, murine collagen-induced arthritis, can be effectively treated by local gene transfer of p21(Cip1) as well as that of p16(INK4a). The anti-arthritic effects were observed even when the treatment was conducted after the arthritis had developed. Furthermore, the effects included suppression of the expression of proinflammatory cytokines such as IL-1ss, IL-6, and TNF-alpha. Our results demonstrate that the ectopic expression of cyclin-dependent kinase inhibitors not only prevents synovial overgrowth but also ameliorates the proinflammatory milieu in the affected joints. The induction of p21(Cip1) in rheumatoid synovial tissues by pharmacological agents may also be an effective strategy to treat rheumatoid arthritis.