Hepatic Immunomodulatory Effect of Belatacept on the TNF-α/IL-6 Pro-Inflammatory Axis and Its Impact on Regulation of MiRNA-146a in Hepatic Injury.

Abstract

Objective: Acute liver injury is associated with a systemic cytokine release that determines the clinical prognosis. Although there are many hepatoprotective drugs, their unique immunomodulatory profiles are still unclear. This study evaluates the therapeutic potential of Belatacept versus Prednisolone on miRNA-146a expression and the pro-inflammatory cytokine cascade in a rat model of Concanavalin A-induced hepatic damage.

Materials and methods: The animal model of liver injury was induced in adult male Wistar rats by dividing them in 4 groups: normal controls, liver injury, prednisolone, and belatacept-treated groups. The serum levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were used to determine the systemic inflammation and were measured by enzyme-linked immunosorbent assay. RT-qPCR was used to quantify the expression of hepatic miRNA-146a. Statistical significance was established by using one-way ANOVA (p < 0.05).

Results: TNF-α and IL-6 levels in serum increased significantly, in response to inducing hepatic damage (p < 0.05). Alongside this, a notable dysregulation of miRNA-146a was detected. Belatacept treatment successfully inhibited the cytokine systemic response, bringing IL-6 down to levels that were statistically more significant than those attained by prednisolone (p < 0.01), while TNF-α reduction was comparable in both groups (p > 0.05). Additionally, Belatacept treatment effectively upregulates miRNA-146a levels, achieving a restoration profile which was statistically more significant than prednisolone (p < 0.01).

Conclusion: These findings show that belatacept has stronger immunomodulatory action when compared with standard therapy. Belatacept is a promising new treatment option for liver-driven systemic inflammation which acts by inhibiting the TNF-α/IL-6 axis and modulating miRNA-146a.