RRC ID 12034
Author Nonomura Y, Nagasaka K, Hagiyama H, Sekine C, Nanki T, Tamamori-Adachi M, Miyasaka N, Kohsaka H.
Title Direct modulation of rheumatoid inflammatory mediator expression in retinoblastoma protein-dependent and -independent pathways by cyclin-dependent kinase 4/6.
Journal 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.
Volume 54(7)
Pages 2074-83
Published 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
Times Cited 21
DNA material Ax1w1 (RDB01746)