PROTEOSOME INHIBITOR ENHANCES ANTI-FIBROTIC EFFICACY OF TLR3-STIMULATING AGENT IN HEPATIC FIBROSIS

Abstract

Background and Aims: Activated hepatic Natural Killer (NK) cells can attenuate hepatic fibrosis by killing activated hepatic stellate cells (HSCs) in a TRAIL-dependent manner. Since proteosome inhibitors can induce TRAIL receptor expression and TLR3 stimulation can activate NK cells, we attempted to examine if simultaneous treatment of proteosome inhibitor may enhance anti-fibrotic efficacy of TLR3 stimulating agent in hepatic fibrosis. Methods: Hepatic fibrosis in vivo model was established in 8 BALB/c mice in each group by injecting thioacetamide intraperitoneally three times per week for 6 weeks. Polyinosinic:polycytidylic acid (poly I:C) was used as an NK cell-activating agent, which is mediated via TLR3 stimulation, and Bortezomib was used as a proteosome inhibitor. Poly I:C and Bortezomib were administered intraperitoneally for 5 weeks. Hepatic fibrosis was assessed by morphometric analysis of histological findings. HSC apoptosis was assessed by double staining for TUNEL and a smooth muscle actin. Results: There were no differences in mortality: 3 died in control mice, mice treated with poly I:C and mice treated with poly I:C + Bortezomib, and 2 died in mice treated with Bortezomib. There were no significant differences in mean body weight among 4 groups. AST and ALT were higher in control mice and mice treated with Bortezomib than in mice treated with poly I:C and mice treated with poly I:C + Bortezomib. The extent of collagen deposition was significantly decreased in mice treated with poly I:C + Bortezomib as compared to control or single compoundtreated mice (Figure 1, *p<0.001). The number of TUNEL-positive HSCs was markedly increased in mice treated with poly I:C + Bortezomib as compared to control or single compound-treated mice. Conclusions: These results demonstrate that proteosome inhibitor enhances anti-fibrotic efficacy of TLR3-stimulating agent in in vivo model of hepatic fibrosis. Therefore, this combination strategy may therapeutically be implicated in hepatic fibrosis.