Peer-Reviewed Journal Details
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Wang, JH,Redmond, HP,Watson, RWG,Condron, C,Bouchier-Hayes, D;
1999
May
Shock
Involvement of tyrosine protein kinase in INF-gamma-induced human endothelial cell apoptosis
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INTERFERON-GAMMA IFN-GAMMA THYMOCYTE APOPTOSIS DNA FRAGMENTATION DEATH NECROSIS MECHANISMS INHIBITORS PREVENTION INDUCTION
11
311
318
Although it is well recognized that interferon-gamma (IFN-gamma) is involved in the development of systemic inflammatory response syndrome, a condition characterized by loss of endothelial barrier function, whether or not IFN-gamma has any direct effect on endothelial cell (EC) death is unclear. Furthermore, which signal transduction pathway involved in IFN-gamma-induced EC apoptosis remains to be elucidated. To answer these questions, we investigated the effect of IFN-gamma on EC death (apoptosis versus necrosis) and the underlying signal transduction pathway responsible for IFN-gamma-induced EC apoptosis. IFN-gamma resulted in a dose-dependent increase in EC apoptosis after 24 h incubation (p < .05). However, IFN-gamma did not induce EC necrosis. Tumor necrosis factor-alpha (TNF-alpha), but not lipopolysaccharide (LPS), had a augmentative effect on IFN-gamma-induced EC apoptosis (p < .05), while both of them alone failed to induce EC apoptosis. These results indicate that exposure of EC to IFN-gamma can cause apoptosis rather than necrosis. Both calcium ionophore, A23187, and the protein kinase C (PKC) activator phorbol-myristate-acetate (PMA) had a synergistic effect on IFN-gamma-induced EC apoptosis (p < .05). However, neither the calcium chelator 1,2-bis 2-aminophenoxy ethane-N,N,N',N'-tetraacetic acid (BAPTA), nor the PKC inhibitor 1 -5-isoquinolinysulfonyl 2-methyl piperazine (H-7) attenuated IFN-gamma-induced EC apoptosis. Three specific tyrosine protein kinase (TPK) inhibitors, herbimycin A, tyrphostin, and genistein, significantly inhibited IFN-gamma-induced EC apoptosis in a dose-dependent fashion (p < .05). Furthermore, the activation of TPK in EC by IFN-gamma was completely abrogated by these TPK inhibitors. These findings suggest that the signal transduction pathway required for induction of EC apoptosis by IFN-gamma is TPK dependent and is independent of calcium and PKC.
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