Drs. Nonomura and Nagasaka contributed equally to this work.
Direct modulation of rheumatoid inflammatory mediator expression in retinoblastoma protein–dependent and –independent pathways by cyclin-dependent kinase 4/6
Article first published online: 26 JUN 2006
Copyright © 2006 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 54, Issue 7, pages 2074–2083, July 2006
How to Cite
Nonomura, Y., Nagasaka, K., Hagiyama, H., Sekine, C., Nanki, T., Tamamori-Adachi, M., Miyasaka, N. and Kohsaka, H. (2006), Direct modulation of rheumatoid inflammatory mediator expression in retinoblastoma protein–dependent and –independent pathways by cyclin-dependent kinase 4/6. Arthritis & Rheumatism, 54: 2074–2083. doi: 10.1002/art.21927
- Issue published online: 27 JUN 2006
- Article first published online: 26 JUN 2006
- Manuscript Accepted: 20 MAR 2006
- Manuscript Received: 1 AUG 2005
- Ministry of Health, Labor, and Welfare of Japan
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Kato Memorial Bioscience Foundation
It is known that the cyclin-dependent kinase inhibitor (CDKI) gene p21Cip1 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).
Genes for the CDKIs p16INK4a and p18INK4c, 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.
Transfer of the p16INK4a and p18INK4c genes and CDK4I suppressed the production of MMP-3 and MCP-1. Unlike p21Cip1, 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.
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.