IL-37 ameliorates acetaminophen-induced acute liver injury by limiting liver inflammation

Abstract Objective: Acetaminophen (APAP) overdose can lead to necrosis of liver parenchymal cells, causing aseptic inflammation and potential liver injury or failure. While IL-37 is known as an anti-inflammatory cytokine, its role and novel mechanism in drug-induced liver injury (DILI) are still unknown. Methods: Male C57BL/6 mice were randomly assigned to four groups (n=10 per group): Sham group, sham+IL-37 group, drug-induced liver injury model group (model group), and model+IL-37 group. The mice were injected with APAP and sacrificed after 4 or 24 hours to observe liver injury and assess related physiological and biochemical indicators.The serum levels of ALT, AST, and LDH were measured using an automated biochemical analyzer. The levels of IL-6, IL-10, TGF-β1, TNF-α and the content of p4502E1(CYP2E1) were detected by ELISA and fluorescence quantitative PCR, respectively. Immunohistochemistry was employed to detect the expression levels of MPO and Ly-6G in liver tissues. Spectrophotometry was used to measure the levels of SOD, MDA, and T-GSH in order to investigate the potential protective effect and underlying mechanism of IL-37 against APAP-induced acute liver injury. Results: Treatment with IL-37 significantly alleviated liver injury in the IL-37+ model group compared to the model group. The IL-37+ model group exhibited reduced neutrophil infiltration and levels of pro-inflammatory cytokines (IL-6, TNF-α), while anti-inflammatory factors (IL-10, TGF-β1) were upregulated. Moreover, the IL-37+ model group showed significant decreases in malondialdehyde (MDA) and superoxide dismutase (SOD) levels compared to the model group. Our results indicated no significant difference in the relative expression level of CYP2E1 mRNA and GSH level between the model group and the therapy group, at both 4 and 24 hours after APAP exposure. Conclusion: IL-37 serves a protective role in APAP-induced liver injury by inhibiting inflammation and oxidative stress.