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Updated: Sep 8, 2026
Bile Duct Ligation in Mice: Induction of Inflammatory Liver Injury and Fibrosis by Obstructive Cholestasis
Published on: February 10, 2015
Targeting cIAPs attenuates CCl4-induced liver fibrosis by increasing MMP9 expression derived from neutrophils
Yi Wu1, Suwen Lu1, Xuan Huang1
1State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Aims:
Liver fibrosis is a growing public health concern without effective medical treatment. Recent reports have indicated that inhibitors of apoptosis proteins (IAPs) were potential targets for idiopathic pulmonary fibrosis therapy. However, their roles have not been well identified in liver fibrosis.
Methods:
The expression of IAPs were examined in human liver tissue and experimental mouse models. Liver fibrosis in CCl4-induced mouse models were investigated by Sirius red staining, RT-PCR, Western blotting after hepatocytes-specific cIAP2 knockout or IAPs inhibitor APG-1387 treatment. The underlying molecular mechanism of APG-1387 action was explored by apoptosis analysis, matrix metalloprotein 9 (MMP9) inhibition, neutrophils depletion, and CC Motif Chemokine Ligand 5 (CCL5) gene knockout in vitro and in vivo.
Findings:
Our study showed that increased expression of cIAP2 was associated with liver fibrosis severity in liver tissues. Deletion of cIAP2 from hepatocytes or degrading cIAPs by APG-1387 ameliorated liver fibrosis induced by CCl4. APG-1387 treatment exhibited increased expression of MMP9 and resulted in higher ratio of MMP9 to tissue inhibitor of metalloproteinase-1. MMP9 was mainly derived from CCL5 chemotactic neutrophils. Further, MMP9 inhibition by CTT peptide, neutrophil depletion by Ly6G antibody or CCL5 deficiency blocked the anti-fibrotic effects of APG-1387 in vivo.
Significance:
These results suggested that cIAPs, especially cIAP2, might play a novel role in the pathogenesis of liver fibrosis, and targeting cIAPs represented a promising therapeutic strategy for liver fibrosis by increasing MMP9 expression induced by CCL5 chemotactic neutrophils.
Insights
Targeting inhibitors of apoptosis proteins (IAPs), particularly cIAP2, shows promise for treating liver fibrosis. This approach increases matrix metalloproteinase 9 (MMP9) via CCL5-attracted neutrophils, offering a new therapeutic strategy.
Area of Science:
- Hepatology and immunology
- Molecular biology
- Fibrosis research
Background:
- Liver fibrosis is a significant health issue lacking effective treatments.
- Inhibitors of Apoptosis Proteins (IAPs) are implicated in idiopathic pulmonary fibrosis but their role in liver fibrosis is unclear.
Purpose of the Study:
- To investigate the role of IAPs in liver fibrosis pathogenesis.
- To explore IAPs as a potential therapeutic target for liver fibrosis.
Main Methods:
- Examined IAP expression in human liver tissues and CCl4-induced mouse models.
- Assessed liver fibrosis severity following hepatocyte-specific cIAP2 knockout or treatment with IAP inhibitor APG-1387.
- Investigated APG-1387's mechanism via apoptosis, MMP9, neutrophil, and CCL5 analyses.
Main Results:
- Increased cIAP2 expression correlated with liver fibrosis severity.
- Hepatocyte cIAP2 deletion or APG-1387 treatment ameliorated CCl4-induced liver fibrosis.
- APG-1387 increased MMP9, primarily neutrophil-derived via CCL5, which was crucial for its anti-fibrotic effect.
Conclusions:
- cIAPs, especially cIAP2, play a novel role in liver fibrosis.
- Targeting cIAPs is a promising therapeutic strategy for liver fibrosis.
- The mechanism involves increased MMP9 expression mediated by CCL5-attracted neutrophils.
