論文 - 詳細
RRC ID | 12034 |
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著者 | Nonomura Y, Nagasaka K, Hagiyama H, Sekine C, Nanki T, Tamamori-Adachi M, Miyasaka N, Kohsaka H. |
タイトル | Direct modulation of rheumatoid inflammatory mediator expression in retinoblastoma protein-dependent and -independent pathways by cyclin-dependent kinase 4/6. |
ジャーナル | Arthritis Rheum |
Abstract |
OBJECTIVE:It is known that the cyclin-dependent kinase inhibitor (CDKI) gene p21(Cip1) suppresses rheumatoid inflammation by down-modulating type I interleukin-1 receptor (IL-1RI) expression and inhibiting JNK activity. The purpose of this study was to determine whether CDK activity directly modulates the production of inflammatory molecules in patients with rheumatoid arthritis (RA). METHODS:Genes for the CDKIs p16(INK4a) and p18(INK4c), a constitutively active form of retinoblastoma (RB) gene product, cyclin D1, and CDK-4, were transferred into RA synovial fibroblasts (RASFs). RASFs were also treated with a synthetic CDK-4/6 inhibitor (CDK4I). Levels of matrix metalloproteinase 3 (MMP-3), monocyte chemoattractant protein 1 (MCP-1), and IL-1RI expression were determined by Northern blotting, real-time polymerase chain reaction analysis, and enzyme-linked immunosorbent assay. CDKIs were immunoprecipitated to reveal their association with JNK. RESULTS:Transfer of the p16(INK4a) and p18(INK4c) genes and CDK4I suppressed the production of MMP-3 and MCP-1. Unlike p21(Cip1), neither CDKI gene inhibited IL-1RI or JNK. The expression of MMP-3 was up-regulated when CDK-4 activity was augmented. This regulation functioned at the messenger RNA (mRNA) level in MMP-3, but not in MCP-1. Transfer of active RB suppressed the production of MMP-3 and MCP-1 without changing their mRNA levels. CONCLUSION:CDK-4/6 modulated the production of MMP-3 and MCP-1. MMP-3 production was regulated primarily at the mRNA level in an RB-independent manner, whereas MCP-1 production was controlled posttranscriptionally by RB. These results show that cell cycle proteins are associated with control of mediators of inflammation through multiple pathways. |
巻・号 | 54(7) |
ページ | 2074-83 |
公開日 | 2006-7-1 |
DOI | 10.1002/art.21927 |
PMID | 16802342 |
MeSH | Arthritis, Rheumatoid / genetics* Arthritis, Rheumatoid / pathology Arthritis, Rheumatoid / physiopathology* Cell Proliferation Cells, Cultured Chemokine CCL2 / genetics Chemokine CCL2 / metabolism* Cyclin D1 / genetics Cyclin D1 / metabolism Cyclin-Dependent Kinase 4 / antagonists & inhibitors Cyclin-Dependent Kinase 4 / genetics Cyclin-Dependent Kinase 4 / metabolism* Cyclin-Dependent Kinase 6 / antagonists & inhibitors Cyclin-Dependent Kinase 6 / genetics Cyclin-Dependent Kinase 6 / metabolism* Cyclin-Dependent Kinase Inhibitor p16 / genetics Cyclin-Dependent Kinase Inhibitor p16 / physiology Cyclin-Dependent Kinase Inhibitor p18 / genetics Cyclin-Dependent Kinase Inhibitor p18 / physiology Cyclin-Dependent Kinase Inhibitor p21 / genetics Cyclin-Dependent Kinase Inhibitor p21 / physiology Fibroblasts / drug effects Fibroblasts / metabolism Fibroblasts / pathology Gene Expression Regulation / drug effects Gene Expression Regulation / physiology Humans MAP Kinase Kinase 4 / genetics MAP Kinase Kinase 4 / metabolism Matrix Metalloproteinase 3 / genetics Matrix Metalloproteinase 3 / metabolism* RNA, Messenger / genetics RNA, Messenger / metabolism Receptors, Interleukin-1 / genetics Receptors, Interleukin-1 / metabolism Receptors, Interleukin-1 Type I Retinoblastoma Protein / genetics Retinoblastoma Protein / physiology* Synovial Membrane / drug effects Synovial Membrane / metabolism Synovial Membrane / pathology |
引用数 | 21 |
WOS 分野 | RHEUMATOLOGY |
リソース情報 | |
遺伝子材料 | Ax1w1 (RDB01746) |