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Inhibition of IRF3 expression reduces TGF-β1-induced proliferation of hepatic stellate cells
Ming-ming Ni1,2, Tao Xu1,2, Ya-rui Wang1,2
1School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, 230032, China.
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.
Insights
Interferon regulatory factor 3 (IRF3) promotes liver fibrosis by increasing hepatic stellate cell proliferation. Inhibiting IRF3 reduces fibrosis markers and halts HSC proliferation, offering a potential therapeutic target for liver fibrosis.
Area of Science:
- Hepatology and Immunology
- Cell Biology
- Molecular Medicine
Background:
- Liver fibrosis is a significant clinical challenge with hepatic stellate cell (HSC) activation as a key driver.
- While Interferon regulatory factor 3 (IRF3) is implicated in other fibrotic conditions and liver diseases, its specific role in liver fibrosis is not well understood.
- Targeting HSC proliferation is a promising strategy for reversing liver fibrosis.
Purpose of the Study:
- To investigate the role of Interferon regulatory factor 3 (IRF3) in the proliferation and apoptosis of human hepatic stellate cells (HSCs).
- To elucidate the mechanism by which IRF3 influences liver fibrosis progression.
- To evaluate IRF3 as a potential therapeutic target for liver fibrosis.
Main Methods:
- Utilized human HSC cell line (LX-2) and manipulated IRF3 expression using small interfering RNA (siRNA) and overexpression techniques.
- Assessed the expression levels of fibrosis markers, including type I collagen (Col1a1) and α-smooth muscle actin (α-SMA).
- Investigated the impact of IRF3 modulation on HSC proliferation and apoptosis, and explored its connection to the AKT signaling pathway.
Main Results:
- IRF3 expression was upregulated in HSCs stimulated with TGF-β1.
- IRF3 inhibition (using IRF3-siRNA) decreased Col1a1 and α-SMA expression and suppressed TGF-β1-induced HSC proliferation while increasing apoptosis.
- IRF3 overexpression led to increased Col1a1 and α-SMA expression and enhanced HSC proliferation.
- IRF3 appears to regulate HSC proliferation via the AKT signaling pathway.
Conclusions:
- IRF3 plays a critical role in regulating TGF-β1-induced human HSC proliferation and apoptosis.
- IRF3 acts as a pro-fibrotic factor in the liver, promoting HSC activation and proliferation.
- IRF3, potentially through the AKT signaling pathway, represents a novel therapeutic target for managing liver fibrosis.
