Regulation of NF-κB activation, inflammation and apoptosis after TNF stimulation. Upon TNF binding to its receptor (TNFR1), the IKK complex (IKK1, IKK2 and NEMO) becomes activated via adapter proteins like TRAF2 and RIP and mediates phosphorylation, ubiquitination and proteasome-mediated degradation of the inhibitory protein IκBα. This action liberates the p50–p65 NF-κB dimer and unmasks its nuclear localization site, resulting in NF-κB translocation to the nucleus, subsequent transcription of antiapoptotic and inflammatory genes and repression of JNK activation. These NF-κB-dependent signals are “counterbalancing” the TNF-induced cleavage of caspases like caspase-8 and the induction of apoptosis. Abbreviations: FADD, Fas-associated death domain; IKK, inhibitory κB kinase; IκB, inhibitor of κB; JNK, c-Jun-(N)-terminal kinase; NEMO, NF-κB essential modulator; NF-κB, nuclear factor κB; p, phosphorylation; TAK1, TGF-β-activated kinase 1; TNF, tumor necrosis factor; TNF-R1, TNF-receptor 1; TRADD, TNF-receptor-associated death domain; TRAF2, TNF-receptor-associated factor 2; RIP, receptor-interacting protein; Ub, ubiquitination

The contribution of NF-κB to hepatic stellate cell activation and survival. LPS activates TLR4 on quiescent HSCs to downregulate the inhibitory TGFβ pseudoreceptor BAMBI, and to increase chemotaxis of Kupffer cells in an NF-κB-dependent manner. Recruited Kupffer cells then release TGFβ, which activates HSCs in an unrestricted manner owing to low levels of BAMBI. Once HSCs have become activated, NF-κB plays an additional important role by enhancing their survival. The NF-κB activation in activated hepatic stellate cells is mediated by LPS, mediators released from Kupffer cells (such as IL-1β and TNF) and angiotensin II, which is released and acts on HSCs in an autocrine manner. Together, the increased activation and survival of HSCs result in increased numbers of activated HSCs in the liver and increased deposition of extracellular matrix. Abbreviations: AngII, angiotensin II; HSC, hepatic stellate cell; IL-1, interleukin 1; LPS, lipopolysaccharide; NF-κB, nuclear factor κB; TLR4, Toll-like receptor 4; TGFβ, transforming growth factor β, TGFβR1, transforming growth factor β receptor 1; TNF, tumor necrosis factor.

NF-κB contributes to hepatocarcinogenesis in the setting of chronic injury, inflammation and fibrosis. Low levels of NF-κB exacerbate injury induced by hepatitis viruses, alcohol, fat, LPS or carcinogens. However, complete absence of NF-κB (achieved by deletion of Tak1 or Nemo in mouse models) is sufficient to initiate apoptosis of hepatocytes even without these triggers, probably because low levels of LPS still reach the liver. Increased hepatic injury leads to stimulation of regenerative responses in progenitor cells and activation of Kupffer cells by IL-1α released from dying hepatocytes. In turn, these processes stimulate NF-κB activation in Kupffer cells and the release of mediators such as IL-1β and TNF. These mediators may induce further hepatocyte injury, IL-1α release and regenerative responses, leading to a vicious circle of injury, inflammation and regeneration. At the same time, LPS from the intestinal microbiota and TNF and IL-1β from Kupffer cells act on HSCs to promote their activation and survival. Activated HSCs and/or hepatic myofibroblasts produce extracellular matrix, which changes the hepatic microenvironment. Abbreviations: HCC, hepatocellular carcinoma; HSC, hepatic stellate cell; IL, interleukin; LPS, lipopolysaccharide; NF-κB, nuclear factor κB; TNF, tumor necrosis factor.