HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Related articles in The JI Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nonomura, Y. Articles by Miyasaka, N. Search for Related Content PubMed PubMed Citation Articles by Nonomura, Y. Articles by Miyasaka, N.

Gene Transfer of a Cell Cycle Modulator Exerts Anti-Inflammatory Effects in the Treatment of Arthritis ¹

Department of Bioregulatory Medicine and Rheumatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

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-3, 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-B 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.

Related articles in The JI:

IN THIS ISSUE

The JI 2003 171: 4471-4472. [Full Text]  

This article has been cited by other articles:

				A. P. Bastos, K. Piontek, A. M. Silva, D. Martini, L. F. Menezes, J. M. Fonseca, I. I. Fonseca, G. G. Germino, and L. F. Onuchic Pkd1 Haploinsufficiency Increases Renal Damage and Induces Microcyst Formation following Ischemia/Reperfusion J. Am. Soc. Nephrol., November 1, 2009; 20(11): 2389 - 2402. [Abstract] [Full Text] [PDF]

				C. Sekine, T. Sugihara, S. Miyake, H. Hirai, M. Yoshida, N. Miyasaka, and H. Kohsaka Successful Treatment of Animal Models of Rheumatoid Arthritis with Small-Molecule Cyclin-Dependent Kinase Inhibitors J. Immunol., February 1, 2008; 180(3): 1954 - 1961. [Abstract] [Full Text] [PDF]

				J. C. Scatizzi, J. Hutcheson, E. Bickel, J. M. Woods, K. Klosowska, T. L. Moore, G. K. Haines III, and H. Perlman p21Cip1 Is Required for the Development of Monocytes and Their Response to Serum Transfer-induced Arthritis Am. J. Pathol., May 1, 2006; 168(5): 1531 - 1541. [Abstract] [Full Text] [PDF]

				A Radbruch and A Thiel Cell therapy for autoimmune diseases: does it have a future? Ann Rheum Dis, November 1, 2004; 63(suppl_2): ii96 - ii101. [Abstract] [Full Text] [PDF]