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

NF‐κB activation plays a crucial role in anti‐apoptotic responses in response to the apoptotic signaling during tumor necrosis factor (TNF)‐α stimulation. TNF‐α induces apoptosis sensitive to the hepatitis B virus (HBV) infected cells, despite sustained NF‐κB activation. Our results indicate that the HBV infection induces sustained NF‐κB activation, in a manner similar to the TNF‐α 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‐κB activation during TNF‐α 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‐α stimulation, (ii) the incremental change in IKK‐p determines the amplitudes of active NF‐κB oscillation, and (iii) the steady state level of IKK‐p after the incremental change determines the period of active NF‐κB oscillation. Based on experiments, we observed that the initial level of IKK‐p was upregulated and the active NF‐κB oscillation showed smaller amplitudes for a shorter period in HepG2.2.15 cells (HBV‐producing cells) during TNF‐α stimulation, as was indicated by the computational simulations. Furthermore, we found that during TNF‐α stimulation, NF‐κB‐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‐κB and thereby could affect NF‐κB‐regulated anti‐apoptotic gene expressions. Finally, we postulate that the sensitive apoptotic response of HBV‐infected cells to TNF‐α stimulation is governed by the dynamic patterns of active NF‐κB based on IKK‐p level changes.