Heat shock protein 90 is required for increased DNA binding activity of activator protein-1, a heterodimer of Fos/JunD, in rheumatoid synovial cells under inflammatory stimuli.
We have studied the DNA binding profiles of activator protein-1 (AP-1) involved in synovial overgrowth and osteoporosis in rheumatoid arthritis (RA) in relation to the molecular chaperon heat shock protein 90 (HSP90). The AP-1 binding activity of the nuclear extracts of rheumatoid synovial cells was basically increased as compared with osteoarthritic synovial cells. Upon stimulation with inflammatory cytokines IL-1beta or TNFalpha, the AP-1 binding activity was further increased in rheumatoid synovial cells, and increased AP-1 protein was composed as heterodimers of Fos and JunD which was not known before as a major component of AP-1 in rheumatoid synovial cells. The increase of AP-1 binding activity as induced by inflammatory cytokines was specifically inhibited by geldanamycin, radicicol or herbimycin A, specific inhibitors of HSP90, while AP-1 protein was not decreased by geldanamycin. Further, HSP90 protein was not decreased by the inhibitors. The findings indicate that HSP90 is required for increased AP-1 binding activity of rheumatoid synovial cells under inflammatory stimuli and that AP-1 binding activity is inhibited by functionally inactivating HSP90 with the inhibitors.
Murata
Miki
M
Department of Rheumatology, Kobe University FHS School of Medicine, Kobe, Japan.
Miura
Yasushi
Y
Hashiramoto
Akira
A
Kitamura
Hitomi
H
Kawasaki
Hiroki
H
Shiozawa
Kazuko
K
Yoshiya
Shinichi
S
Baba
Hisamitsu
H
Chihara
Kazuo
K
Shiozawa
Shunichi
S
D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D016207:Cytokines; D018841:HSP90 Heat-Shock Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D004247:DNA