Fig. 8
A schematic presentation of the mechanism underlying TNFα cytotoxicity in vivo. Left panel, non-cytotoxic dose TNFα-induced apoptosis is typically suppressed by IKK-mediated activation of NF-κB and inactivation of BAD.14 Under this condition, non-cytotoxic dose TNFα does induce limited BAD released from the cytoskeleton to the cytosol via transient and modest activation of the Src-p190GAP-RhoA pathway and subsequently all cytosolic BAD is phosphorylated and inactivated by IKK, thereby there is no apoptosis. Right panel, although cytotoxic dose TNFα induces slightly higher level activation of IKK, which is still capable of activating NF-κB and inactivating BAD to inhibit apoptosis, it induces massive BAD release from the cytoskeleton to the cytosol through prolonged and strong activation of the Src-p190GAP-RhoA pathway. Under this condition, the amount of BAD in the cytosol becomes much more than IKK can phosphorylate. Consequently, non-phosphorylated BAD translocates to mitochondria to induce apoptosis despite concurrent activation of the IKK-NF-κB pathway. Polymicrobial infection and LPS utilize the same mechanism as cytotoxic dose TNFα to induce septic shock. The red arrows were thicker in Right panel than the ones in Left panel, indicating that cytotoxic dose TNFα induces prolonged and strong activation of the Src-p190GAP-RhoA pathway than non-cytotoxic dose TNFα. See the text for additional details
