Figure 2.

Ablation of TAK1 in hepatocytes induces spontaneous liver injury, inflammation, fibrosis, and cancer. Spontaneous hepatocyte death occurs in hepatocyte specific TAK1-deficient mice followed by the release of damage-associated molecular patterns (DAMPs) which stimulate Kupffer cells to produce TNF-α. This TNF-α further induces cell death in TAK1-deficient hepatocytes lacking activation of NF-κB and JNK. TNF-α, IL-1β, and IL-6 released from Kupffer cells cause liver inflammation. Kupffer cell-derived TGF-β stimulates hepatic stellate cells resulting in fibrogenesis. The persistent hepatocyte death and uncontrolled compensatory proliferation in the livers of hepatocyte specific TAK1-deficient mice induce the reactivation of onco-fetal liver genes that are associated with the initiation of hepatic carcinogenesis.