Hepatocyte growth factor-mediated apoptosis mechanisms of cytotoxic CD8+ T cells in normal and cirrhotic liver

Abstract

Intrahepatic stem/progenitor cells and cytotoxic CD8+ T cells (CD8+ T cells) in the cirrhotic liver undergo apoptosis potentially facilitating progression to cancer. Here, we report that hepatocyte growth factor (HGF) signaling plays an important role in promoting normal and damaged liver CD8+ T cell Fas-mediated apoptotosis through its only receptor c-Met. In addition to binding with HGF, c-Met also binds to Fas as a complex. Using a diethylnitrosamine (DEN)-induced liver fibrosis/cirrhosis mouse model, immunofluostaining and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining, we identified significantly increased HGF secretion at 10 weeks post-DEN, the liver cirrhotic phase (LCP), compared to it at 3 weeks post-DEN, the liver fibrotic phase (LFP). Correspondingly, difference CD8+ T cell proliferation and apoptosis were noted in the two phases, Interestingly, staining and TUNEL identified that higher smooth muscle actin (α-SMA)+ cell apoptosis, a marker for hepatic stellate cell (HSC) in the LFP compared to their in the LCP, suggesting that beneficial correlation of HGF, CD8+ T cells and HSC in improving fibrotic load during damaged liver repair. In cultures, up to 200 ng/mL amounts of recombinant HGF the naive mouse splenic CD8+ T cells (n-msCD8+ T cells) death, 400 ng/mL rHGF show directly activated death-inducing signaling complex (DISC) to recruit FADD and caspase-8 in both nsCD8+ T cells and healthy human peripheral blood CD8+ T cells (hp-CD8+ T cells), suggesting Fas-mediated apoptosis, may suggest the regulating role of HGF signaling in hepatic homeostasis.