Synergistic induction of apoptosis of rheumatoid arthritis synovial cells by H(2)O(2) and N-acetyl-leucyl-leucyl-norleucinal.
The effects of proteolysis inhibitors on hydrogen peroxide (H(2)O(2))-induced apoptosis were examined in cultured human synovial cells of rheumatoid arthritis (RA) patients. RA synovial cells were resistant to apoptosis induced by H(2)O(2). In the presence of 100 microM N-acetyl-leucyl-leucyl-norleucinal (ALLN, known as calpain inhibitor 1 and also a proteasome inhibitor), but not N-acetyl-leucyl-leucyl-methioninal (ALLM), apoptotic cell death was elicited by 400 microM H(2)O(2) at a concentration that alone never induced cell death. ALLN induced the expression of tumor suppressor p53 protein and p21(WAF-1) protein, probably through inhibition of proteasome. H(2)O(2) further potentiated ALLN-induced p53 expression. H(2)O(2) appeared to activate c-Jun N-terminal kinase (JNK) as well as extracellular signal-regulated kinase (ERK) and AKT. After administration of H(2)O(2) and p53 induction by ALLN, we found that either one alone is insufficient to induce apoptosis of RA synovial cells but their combination synergistically does so. These results suggest that induction of p53 by ALLN may be potentially important for triggering H(2)O(2)-induced apoptosis processes in RA synovial cells.
Akaike
Atsushi
A
Department of Orthopaedic Surgery, Gifu University School of Medicine, 40 Tsukasamachi, Gifu 500-8705, Japan.
Banno
Yoshiko
Y
Osawa
Yousuke
Y
Oshita
Hidefumi
H
Fushimi
Kazunari
K
Kodama
Hirotaka
H
Shimizu
Katsuji
K
D017209:Apoptosis / Q000187:drug effects*; D001172:Arthritis, Rheumatoid / Q000503:physiopathology*; D002154:Calpain / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007976:Leupeptins / Q000494:pharmacology*; D013583:Synovial Membrane / Q000166:cytology*
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; C063261:acetylleucyl-leucyl-norleucinal; D006861:Hydrogen Peroxide; D002154:Calpain