The influence of the signal dynamics of activated form of IKK on NF-kappa B and anti-apoptotic gene expressions: A systems biology approach

Abstract

NF-kappa B activation plays a crucial role in anti-apoptotic responses in response to the apoptotic signaling during tumor necrosis factor (TNF)-alpha stimulation. TNF-alpha induces apoptosis sensitive to the hepatitis B virus (HBV) infected cells, despite sustained NF-kappa B activation. Our results indicate that the HBV infection induces sustained NF-kappa B activation, in a manner similar to the TNF-a stimulation. However, these effects are not merely combined. Computational simulations show that the level of form of the IKK complex activated by phosphorylation (IKK-p) affects the dynamic pattern of NF-kappa B activation during TNF-alpha stimulation in the following ways: (i) the initial level of IKK-p determines the incremental change in IKK-p at the same level of TNF-alpha stimulation, (ii) the incremental change in IKK-p determines the amplitudes of active NF-kappa B oscillation, and (iii) the steady state level of IKK-p after the incremental change determines the period of active NF-kappa B oscillation. Based on experiments, we observed that the initial level of IKK-p was upregulated and the active NF-kappa B oscillation showed smaller amplitudes for a shorter period in HepG2.2.15 cells (HBV-producing cells) during TNF-alpha stimulation, as was indicated by the computational simulations. Furthermore, we found that during TNF-alpha stimulation, NF-kappa B-regulated anti-apoptotic genes were upregulated in HepG2 cells but were downregulated in HepG2.2.15 cells. Based on the previously mentioned results, we can conclude that the IKK-p-level changes induced by HBV infection modulate the dynamic pattern of active NF-kappa B and thereby could affect NF-kappa B-regulated antiapoptotic gene expressions. Finally, we postulate that the sensitive apoptotic response of HBV-infected cells to TNF-alpha stimulation is governed by the dynamic patterns of active NF-kappa B based on IKK-p level changes. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.