Attenuation of CCl4-induced hepatic fibrosis in mice by vaccinating against TGF-?1.

ABSTRACT: Transforming growth factor ?1 (TGF-?1) is the pivotal pro-fibrogenic cytokine in hepatic fibrosis. Reducing the over-produced expression of TGF-?1 or blocking its signaling pathways is considered to be a promising therapeutic strategy for hepatic fibrosis. In this study, we evaluated the feasibility of attenuating hepatic fibrosis by vaccination against TGF-?1 with TGF-?1 kinoids. Two TGF-?1 kinoid vaccines were prepared by cross-linking TGF-?1-derived polypeptides (TGF-?1(25)-[41-65] and TGF-?1(30)-[83-112]) to keyhole limpet hemocyanin (KLH). Immunization with the two TGF-?1 kinoids efficiently elicited the production of high-levels of TGF-?1-specific antibodies against in BALB/c mice as tested by enzyme-linked immunosorbent assay (ELISA) and Western blotting. The antisera neutralized TGF-?1-induced growth-inhibition on mink lung epithelial cells (Mv1Lu) and attenuated TGF-?1-induced Smad2/3 phosphorylation, ?-SMA, collagen type 1 alpha 2 (COL1A2), plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) expression in the rat hepatic stellate cell (HSC) line, HSC-T6. Vaccination against TGF-?1 with the kinoids significantly suppressed CCl4-induced collagen deposition and the expression of ?-SMA and desmin, attenuated hepatocyte apoptosis and accelerated hepatocyte proliferation in BALB/c mice. These results demonstrated that immunization with the TGF-?1 kinoids efficiently attenuated CCl4-induced hepatic fibrosis and liver injury. Our study suggests that vaccination against TGF-?1 might be developed into a feasible therapeutic approach for the treatment of chronic fibrotic liver diseases.

SUBMITTER: Fan X 

PROVIDER: S-EPMC3859579 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature