Article Figures & Data
Figures
- Figure 1.
Regulation of cell death and proliferation by the NF-κB and JNK pathways. Complexes assembled on ligand-bound TNF or TLR and IL-1 receptors mediate TAK1 activation, whose activity is modulated by Cyld. TAK1 phosphorylates IKK-β, which in turn phosphorylates IκB, leading to its ubiquitin-proteosome–mediated degradation and release of NF-κB (p50–p65) factors, which translocate to the nucleus to activate the transcription of prosurvival genes. NF-κB also induces the expression of cFLIP and SOD2, which inhibit apoptosis and reactive oxygen species (ROS) accumulation. TAK1 also phosphorylates MKK4/7, which activates JNK1/2. Short-term JNK activation induces the expression of genes involved in proliferation control, via the phosphorylation-mediated activation of JUN transcription factors. Sustained JNK activation induces the expression of proapoptotic genes, and stabilizes p53 and the Bax/Bak-dependent apoptotic pathway. NF-κB feedback regulates its own activation via modulating Cyld expression and the activation of JNK via activating Gadd45β expression, which inhibits MKK4/7. JNK activation is also modulated by ROS accumulation through dual-specificity phosphatase 1 (DUSP1) phosphatase activity. CASP-3/8, caspase-3/8.
- Figure 2.
Mechanism of cell death–mediated inflammation, fibrosis, and carcinogenesis. Sustained JNK activation causes hepatocyte death. Dying hepatocytes release alarmins/damage-associated molecular patterns (DAMP), which leads to the recruitment of Kupffer cells. NF-κB pathway activation in Kupffer cells leads to the expression and secretion of TGF-β, TNF-α, and IL-6 cytokines. TGF-β activates hepatic stellate cells, resulting in fibrogenesis. TNF-α induces apoptosis in the neighboring hepatocytes. Hepatocytes that escape or do not complete cell death may respond to IL-6 via activation of STAT3, which induces compensatory hepatocyte proliferation. IL-6R, IL-6 receptor.
Volume 19, Issue 11
