Protective Function of Novel Fungal Immunomodulatory Proteins Fip-lti1 and Fip-lti2 from Lentinus tigrinus in Concanavalin A-Induced Liver Oxidative Injury

Fungal immunomodulatory proteins (FIPs) are a class of small proteins that have been extensively studied for their immunomodulatory activities. In this study, two novel FIPs from Lentinus tigrinus were identified and named Fip-lti1 and Fip-lti2. The bioactive characteristics of Fip-lti1 and Fip-lti2 were compared to a well-known FIP (LZ-8 from Ganoderma lucidum) to investigate the effect of Fip-lti1 and Fip-lti2 expression on concanavalin A- (Con A-) induced liver oxidative injury. Both Fip-lti1 and Fip-lti2 protected the livers from Con A-induced necrosis, as evidenced by decreased serum aminotransferase levels (AST, ALT) and relieved liver histology. Levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and oxidative stress (SOD, MDA) were shown to be reduced by expressing Fip-lti1 and Fip-lti2. In addition, the hepatoprotective effect of Fip-lti1, Fip-lti2, and LZ-8 correlated with ameliorating the imbalance of Th1/Th2 (IFN-γ/IL-4). The observed liver protection of Fip-lti1 and Fip-lti2 was mechanistically explored. Treatments with Fip-lti1 and Fip-lti2 regulated GATA3/T-bet expression, activated the decreased Nrf-2/HO-1 pathway, and countered the upregulated NLRP3/ASC/NF-κBp65 signaling in Con A-stimulated liver injury. Nrf2 activation was shown to be involved in the mechanisms underlying the protection of Fip-lti by RNA interference. In conclusion, we identified two new fungal proteins (Fip-lti1 and Fip-lti2) that can protect the liver from Con A-induced liver oxidative injury through the Nrf2/NF-κB/NLRP3/IL-1β pathway