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*Rheumatoid Arthritis
The Journal of Immunology, 2001, 167: 1198-1203.
Copyright © 2001 by The American Association of Immunologists

CD44 Is the Physiological Trigger of Fas Up-Regulation on Rheumatoid Synovial Cells1

Koichi Fujii*, Yuko Fujii*, Stefan Hubscher{dagger} and Yoshiya Tanaka2,*

* First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan; and {dagger} Department of Pathology, University of Birmingham, Birmingham, United Kingdom

CD44 is a ubiquitous molecule known as a hyaluronan receptor. However, the relevance of CD44 to inflammatory processes, for example, rheumatoid synovitis, remains unclear. In this study, we propose a novel function for CD44 using synovial cells from rheumatoid arthritis (RA) patients and demonstrated that CD44 cross-linking augmented Fas expression and subsequent Fas-mediated apoptosis of the cells: 1) cross-linking of CD44 on RA synovial cells markedly augmented Fas expression and its mRNA transcription; 2) engagement of CD44 up-regulated Fas on the cells within 3 h, much more than IL-1{beta} and TNF-{alpha} did; 3) the Fas-mediated early apoptotic change of the cells was amplified by CD44 cross-linking; and 4) hyaluronan, especially when fragmented, also augmented Fas-mediated early apoptosis of the cells. Based on these findings, we postulate a new concept: that interaction of CD44 on RA synovial cells with hyaluronan fragments present in the surrounding extracellular matrix augments Fas expression as well as Fas-mediated apoptosis of synovial cells. This may lead to spontaneous growth arrest through Fas-Fas ligand pathway observed in synovial cells of RA synovitis in vivo.




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