Reference - Detail
|Author||Nonomura Y, Kohsaka H, Nagasaka K, Miyasaka N.|
|Title||Gene transfer of a cell cycle modulator exerts anti-inflammatory effects in the treatment of arthritis.|
Forced expression of a cyclin-dependent kinase inhibitor gene, p21(Cip1) in the synovial tissues was effective in treating animal models of rheumatoid arthritis. Synovial hyperplasia in the treated joints was suppressed, reflecting the inhibitory effect of p21(Cip1) on cell cycle progression. Additionally, lymphocyte infiltration, expression of inflammatory cytokines, and destruction of the bone and cartilage were inhibited. To determine why the cell cycle regulator gene exerted such anti-inflammatory effects, we investigated gene expression by rheumatoid synovial fibroblasts with or without the p21(Cip1) gene transferred. We have found that p21(Cip1) gene transfer down-regulates expression of various inflammatory mediators and tissue-degrading proteinases that are critically involved in the pathology of rheumatoid arthritis. These molecules included IL-6, -8, type I IL-1R (IL-1R1), monocyte chemoattractant protein-1, macrophage inflammatory protein-3alpha, cathepsins B and K, and matrix metalloproteinases-1 and -3. Down-regulation of IL-1R1 by p21(Cip1) resulted in attenuated responsiveness to IL-1. Inhibition of the inflammatory gene expression by p21(Cip1) was seen even when IL-1 is absent. This IL-1R1-independent suppression was accompanied by reduced activity of c-Jun N-terminal kinase, which was associated with p21(Cip1), and inactivation of NF-kappaB and AP-1. These multiple regulatory effects should work in concert with the primary effect of inhibiting cell cycle in ameliorating the arthritis, and suggest a heretofore unexplored relationship between cyclin-dependent kinase inhibitor gene and inflammatory molecules.
|MeSH||Adenoviridae / genetics Anti-Inflammatory Agents, Non-Steroidal* / pharmacology Arthritis, Rheumatoid / enzymology Arthritis, Rheumatoid / immunology Arthritis, Rheumatoid / pathology* Arthritis, Rheumatoid / prevention & control* Cell Cycle / genetics* Cell Cycle / immunology Cells, Cultured Chemokines / antagonists & inhibitors Chemokines / biosynthesis Cyclin-Dependent Kinase Inhibitor p21 Cyclins / genetics* Cyclins / physiology DNA-Binding Proteins / antagonists & inhibitors DNA-Binding Proteins / metabolism Enzyme Inhibitors / pharmacology Fibroblasts / immunology Fibroblasts / metabolism Growth Inhibitors / genetics* Growth Inhibitors / physiology Humans Immunosuppressive Agents / pharmacology Interleukin-6 / antagonists & inhibitors Interleukin-6 / biosynthesis Metalloendopeptidases / antagonists & inhibitors Metalloendopeptidases / biosynthesis NF-kappa B / antagonists & inhibitors NF-kappa B / metabolism RNA, Messenger / antagonists & inhibitors RNA, Messenger / biosynthesis Receptors, Interleukin-1 / antagonists & inhibitors Receptors, Interleukin-1 / biosynthesis Receptors, Interleukin-1 Type I Synovial Fluid / cytology Synovial Fluid / immunology Synovial Fluid / metabolism Transcription Factor AP-1 / antagonists & inhibitors Transcription Factor AP-1 / metabolism Transfection / methods*|
|DNA material||Ax1w1 (RDB1746)|