Abstract
Hepatic fibrosis, characterized by an excessive extracellular matrix (ECM) accumulation, leading to scar-tissue formation is a growing health problem worldwide. Hepatocellular damage due to liver injury triggers inflammation and transdifferentiation of quiescent hepatic stellate cells (HSCs) into proliferative, contractile, and ECM-producing myofibroblasts. Involvement of the Janus kinase (JAK)-2 pathway in the pathogenesis of fibrosis has been reported earlier. However, in this study, we have investigated the effect of selective JAK2 antagonist TG101348 in fibroblasts and inflammatory macrophages and in vivo in an acute carbon tetrachloride-induced liver injury mouse model. In vitro, TG101348 significantly inhibited TGF-β-induced collagen I expression in murine 3T3 fibroblasts. In human HSCs (LX2 cells), TG101348 potently attenuated TGF-β-induced contractility and the protein and gene expression of major fibrotic parameters (collagen I, vimentin, and α-smooth muscle actin). In LPS- and IFN-γ-stimulated inflammatory macrophages, TG101348 significantly reduced the NO release and strongly inhibited the expression of inflammatory markers (inducible nitric oxide synthase, C-C motif chemokine ligand 2, IL-1β, IL-6, and C-C chemokine receptor type 2). In vivo in an acute liver injury mouse model, TG101348 significantly attenuated collagen accumulation and HSC activation. Interestingly, TG101348 drastically inhibited macrophage infiltration and intrahepatic inflammation. Pharmacological inhibition of the JAK2 signaling pathway in activated HSCs and inflammatory macrophages using TG101348 suggests a potential therapeutic approach for the treatment of liver fibrosis.-Akcora, B. O., Dathathri, E., Ortiz-Perez, A., Gabriël, A. V., Storm, G., Prakash, J., Bansal, R. TG101348, a selective JAK2 antagonist, ameliorates hepatic fibrogenesis in vivo.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.