Expression of IL-35 in the Prophase of Liver Failure and its Immune Regulatory Interaction with Glucocorticoids

Introduction: To investigate the immunoregulatory role of interleukin-35 (IL-35) in the prophase of liver failure related to hepatitis B virus (HBV-PLF) and its synergistic mechanism with glucocorticoid treatment. Methods: 22 patients with HBV-PLF (matched with 22 healthy controls) were included. Peripheral blood regulatory T cells (Treg)/helper T cells 17 (Th17) ratio, serum IL-35/IL-17 dynamic changes, and liver function indicators were measured both before and after methylprednisolone treatment (1 mg/kg, 7 days). A concanavalin A-induced PLF mouse model was used to evaluate the effects of IL-35 overexpression, IL-35 neutralizing antibody, and dexamethasone on liver injury, cytokines, and the hepatic immune microenvironment. Results: Compared with healthy controls, patients with HBV-PLF exhibited a significantly reduced Treg/Th17 ratio and elevated serum IL-35 levels at baseline (p < 0.05). Following methylprednisolone treatment, both serum IL-35 levels and the Treg/Th17 ratio increased, with IL-35 levels showing a strong positive correlation with the Treg/Th17 ratio (r = 0.69). In the mouse model, IL-35 overexpression significantly alleviated liver injury, showing a hepatoprotective effect comparable to that of dexamethasone (p > 0.05). This improvement was characterized by decreased alanine aminotransferase levels and improved histopathological scores (p < 0.05). In contrast, administration of an IL-35 neutralizing antibody was found to exacerbate damage. Mechanistic investigations revealed that IL-35 promoted the proportion of hepatic FOXP3+ Treg cells while inhibiting Th17 activation, thereby establishing the Treg/Th17 balance. Discussion: This study demonstrates the dynamic immunoregulatory role of IL-35 in PLF through clinical observations and mechanistic validation in a mouse model. IL-35 was closely associated with restoration of the Treg/Th17 balance and showed hepatoprotective effects comparable to glucocorticoids, suggesting its potential as a target for early immunomodulatory intervention. Conclusion: IL-35 serves as a critical regulator of immune homeostasis in PLF. Glucocorticoids appear to exert their protective effects by upregulating IL-35 expression. Consequently, targeting the IL-35 pathway represents a promising strategy for early intervention in liver failure.