TG101348, a selective JAK2 antagonist, ameliorates hepatic fibrogenesis in vivo

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. FASEB J. 33, 9466–9475 (2019). http://www.fasebj.org

Fedratinib Attenuates Bleomycin-Induced Pulmonary Fibrosis via the JAK2/STAT3 and TGF-β1 Signaling Pathway

“…Fed regulates the secretion of these cytokines, thus transforming the vicious circle to a virtuous one and preventing the epithelial cells from further injury. Our findings are in line with a previous study that Fed inhibits LPS-induced inflammatory cytokine IL-6, IL-1β and TNF-α secretion in macrophages [ 33 ], together suggesting the anti-inflammation effect of Fed.…”

“…These cytokines then activate fibroblasts to become myofibroblasts that in turn secrete collagen and other ECM proteins that stiffen the lung. Blocking JAK2/STAT3 signaling has been demonstrated to reduce both inflammation and fibrosis in murine model [ 12 , 33 ]. Here, we found that Fed reduced bleomycin-induced inflammatory response, decreased infiltration of immune cells and downregulated the secretion of profibrotic cytokines such as TGF-β1, TNF-α, IL-1β and IL-6.…”

Pathophysiology and Treatment Options for Hepatic Fibrosis: Can It Be Completely Cured?

“…Since IRF5 mediates hepatocyte death and liver fibrosis in mice as well as humans, modulation of IRF5 function may be another attractive approach to treat fibrosis. Finally, involvement of the Janus Kinase (JAK)-2 pathway in the pathogenesis of hepatic fibrosis, steatosis, ischemia-perfusion injury and HCC has been observed [ 93 ]. In the liver, the JAK2 pathway plays a critical role in regulation of multiple processes including cell growth, differentiation, proliferation and immune functions by activating growth hormones and cytokines including IFN-γ, IL-4, IL-6, IL-12, IL-13 and leptin [ 94 ].…”

“…In the liver, the JAK2 pathway plays a critical role in regulation of multiple processes including cell growth, differentiation, proliferation and immune functions by activating growth hormones and cytokines including IFN-γ, IL-4, IL-6, IL-12, IL-13 and leptin [ 94 ]. Selective JAK2 antagonist TG1011348 inhibits macrophage infiltration, expression of inflammatory markers and nitric oxide release from macrophages and attenuated HSC activation and collagen accumulation, suggesting its use as a potential therapy [ 93 ].…”

Fibrotic Scar in CNS Injuries: From the Cellular Origins of Fibroblasts to the Molecular Processes of Fibrotic Scar Formation

“…However, excessive and prolonged deposition of these proteins due to an uncontrolled wound healing response leads to fibrosis and fibrotic scar formation that affects the functional restoration of the tissue [ 1 , 2 ]. Apart from fibrosis in injured tissue, fibrosis is common in many pathological conditions, occurring in organs such as the liver [ 3 , 4 , 5 , 6 , 7 ], heart [ 8 , 9 , 10 , 11 , 12 ], kidneys [ 13 , 14 , 15 , 16 , 17 ], lungs [ 18 , 19 , 20 , 21 ], and systemic sclerosis [ 22 , 23 , 24 , 25 ].…”