CD44 is the physiological trigger of Fas up-regulation on rheumatoid synovial cells.
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-1beta 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.
Fujii
K
K
First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.
Fujii
Y
Y
Hubscher
S
S
Tanaka
Y
Y
D000276:Adjuvants, Immunologic / Q000502:physiology; D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006820:Hyaluronic Acid / Q000494:pharmacology; D008024:Ligands; D008970:Molecular Weight; D012333:RNA, Messenger / Q000096:biosynthesis; D013583:Synovial Membrane / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology*; D019014:fas Receptor / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D018960:Hyaluronan Receptors; D008024:Ligands; D012333:RNA, Messenger; D019014:fas Receptor; D006820:Hyaluronic Acid