Inhibition of caspase cascade by HTLV-I tax through induction of NF-kappaB nuclear translocation.
NF-kappaB is required for prevention of apoptosis. We examined the importance of human T-cell leukemia virus-I (HTLV-I) Tax protein to stimulate NF-kappaB nuclear translocation, thus preventing apoptosis. Jurkat cells and JPX-9 cells in which the inducible Tax expression plasmid vector was stably transfected were used in the present study. Both Jurkat and Tax(-) JPX-9 cells had small amounts of basal nuclear NF-kappaB activity. The addition of NF-kappaB inhibitors suppressed NF-kappaB nuclear translocation of the cells, thus inducing apoptosis. Sequential activation of caspases from caspase-8 to caspase-3 was shown during this process. NF-kappaB nuclear translocation in JPX-9 cells was stimulated through Tax expression, and both the activation of caspases and apoptosis induced by NF-kappaB inhibitors were significantly suppressed in the Tax(+) JPX-9 cells. The expression of Bcl-2, Bax, and Bcl-x was not changed among Jurkat, Tax(-) JPX-9, and Tax(+) JPX-9 cells in the presence or absence of NF-kappaB inhibitors. X-chromosome-linked inhibitor of apoptosis (XIAP) protein expression in Tax(-) JPX-9 cells was significantly suppressed by NF-kappaB inhibitors, however, its expression in Tax(+) JPX-9 cells was maintained even by the addition of NF-kappaB inhibitors. Our results suggest that the activation of NF-kappaB via Tax protein in HTLV-I infected cells renders the cells resistant to apoptosis. The expression of anti-apoptotic gene products such as XIAP to suppress caspase cascade, results in an increase of cytokine production and cell proliferation; one of the proposed mechanisms that promotes autoimmune disorders such as Sjögren's syndrome and rheumatoid arthritis found in HTLV-I seropositive subjects.
Kawakami
A
A
The First Department of Internal Medicine, and the Department of Hospital Pharmacy, Nagasaki University School of Medicine, Japan.
Nakashima
T
T
Sakai
H
H
Urayama
S
S
Yamasaki
S
S
Hida
A
A
Tsuboi
M
M
Nakamura
H
H
Ida
H
H
Migita
K
K
Kawabe
Y
Y
Eguchi
K
K
D017209:Apoptosis / Q000502:physiology*; D001692:Biological Transport; D020169:Caspases / Q000502:physiology*; D016356:Gene Products, tax / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000473:pathology* / Q000502:physiology* / Q000821:virology
D016356:Gene Products, tax; D016328:NF-kappa B; D020169:Caspases