Inhibition of IRF3 expression reduces TGF-β1-induced proliferation of hepatic stellate cells

Abstract

Therapeutic management of liver fibrosis remains an unresolved clinical problem. Activation of hepatic stellate cell (HSC) is a pivotal event in the progression of liver fibrosis. Recent reports have showed that inhibition of activated HSC proliferation contributes to the reversal of liver fibrosis. Interferon regulatory factor 3 (IRF3), one member of the interferon regulatory factor (IRF) family, is recently proven to be a critical modulator in cardiac fibrosis. And accumulating evidence demonstrated that IRF3 plays a crucial role in liver diseases, such as hepatic steatosis, liver inflammation, and alcoholic liver injury. However, the understanding of the function of IRF3 in liver fibrosis remains limited. Our results identified the role of IRF3 in regulating human HSC (LX-2 cell) cell proliferation and apoptosis. The present study indicated that the expression of IRF3 was significantly increased in HSCs in response to TGF-β1 stimulation. Moreover, a stable and unlimited source of human HSC, the LX-2 cell line, transfected with IRF3-siRNA significantly decreases the expression level of type I collagen (Col1a1) and α-smooth muscle actin (α-SMA) in activated LX-2 cells. On the contrary, overexpression of IRF3 gives rise to an upregulation of Col1a1 and α-SMA in LX-2 cells, and further promoted HSC proliferation. Moreover, the inhibition of IRF3 significantly suppressed TGF-β1-induced HSC proliferation and increased its apoptosis. Of note, the present study indicated IRF3 may regulate LX-2 cell proliferation by via AKT signaling pathway. In summary, these observations suggest IRF3 may function as a novel regulator to modulate TGF-β1-induced LX-2 proliferation, at least in part, via AKT signaling pathway.

Platyconic Acid A, Platycodi Radix-Derived Saponin, Suppresses TGF-β1-Induced Activation of Hepatic Stellate Cells via Blocking SMAD and Activating the PPARγ Signaling Pathway

“…Besides the TGF-β1-dependent SMAD pathway, HSCs are activated by a TGF-β1-independent non-SMAD pathway, which includes Akt and MAPKs [33,34]. Akt and MAPKs are important mediators of signal transduction involved in the activation of HSCs, which can lead to the regulation of cellular growth, differentiation, and proliferation [35,36]. To examine the effects of PA on TGF-β1-induced phosphorylation of Akt and MAPKs, we first determined the timing of TGF-β1-induced Akt and MAPKs phosphorylation in HSC-T6 cells.…”

Candidate Risk Factors and Mechanisms for Tolvaptan-Induced Liver Injury Are Identified Using a Collaborative Cross Approach

“…Angptl4 controls inflammation and apoptosis in the liver (Guo et al, 2015). Irf3 regulates cytokine levels and plays a role in liver diseases such as steatosis, inflammation, and alcoholic liver injury (Loi et al, 2013;Ni et al, 2015). Itgb5 is a subunit of an integrin receptor involved in cell adhesion, viral entry, and antigen processing (Lyle and McCormick, 2010).…”

Fibronectin Type III Domain-Containing 5 Attenuates Liver Fibrosis Via Inhibition of Hepatic Stellate Cell Activation

“…Activation of HSCs remains a pivotal event in hepatic fibrosis [8,36]. Transformation of HSC to myofibroblasts is a profibrogenic process that increases α-SMA and decreases stored lipid [26].…”