Taurine chloramine inhibits proliferation of rheumatoid arthritis synoviocytes by triggering a p53-dependent pathway.
OBJECTIVE
Taurine chloramine (Tau-Cl), originating from activated neutrophils, possesses antiinflammatory activities. Fibroblast-like synoviocytes (FLS) participate in the chronic synovitis and synovial membrane hyperplasia that are characteristic pathological features of rheumatoid arthritis (RA). The present study was conducted to investigate the mechanism of the Tau-Cl effect on the proliferation of these cells in culture.


METHODS
FLS were stimulated in vitro with platelet derived growth factor (PDGF) alone or together with Tau-Cl. Cell proliferation was evaluated by counting the total and dividing cell numbers and by measurement of (3)H-thymidine incorporation. Expression of the key cell-cycle regulators was evaluated at the protein (Western blotting) and/or mRNA (RT-PCR) levels.


RESULTS
Treatment of RA FLS with Tau-Cl (200-500 microM) resulted in an early nuclear accumulation of p53 tumor suppressor protein. Moreover, Tau-Cl inhibited PDGF-triggered cell proliferation (IC(50) value approximately 250-300 microM), accompanied by characteristic modulation of p53 transcriptional targets: down-regulation of proliferating cell nuclear antigen (PCNA) and survivin, and concomitant up-regulation of p21 mitotic inhibitor.


CONCLUSIONS
We propose that Tau-Cl inhibits proliferation of RA FLS by triggering a p53-dependent cell-cycle arrest and conclude that this compound suppresses pathways in FLS that are known to contribute to the pathology of RA.
Kontny
E
E
Department of Pathophysiology and Immunology, Institute of Rheumatology, Spartafska 1, 02-637, Warsaw, Poland. zpatiir@warman.com.pl
Rudnicka
W
W
Chorazy-Massalska
M
M
Marcinkiewicz
J
J
Maśliński
W
W
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007717:Knee; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000077022:Survivin; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism; D013654:Taurine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000893:Anti-Inflammatory Agents; C107489:BIRC5 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013654:Taurine; C043410:N-chlorotaurine