Bee Venom Phospholipase A2 Protects against Acetaminophen-Induced Acute Liver Injury by Modulating Regulatory T Cells and IL-10 in Mice

Abstract

The aim of this study was to investigate the protective effects of phospholipase A2 (PLA2) from bee venom against acetaminophen-induced hepatotoxicity through CD4+CD25+Foxp3+ T cells (Treg) in mice. Acetaminophen (APAP) is a widely used antipyretic and analgesic, but an acute or cumulative overdose of acetaminophen can cause severe hepatic failure. Tregs have been reported to possess protective effects in various liver diseases and kidney toxicity. We previously found that bee venom strongly increased the Treg population in splenocytes and subsequently suppressed immune disorders. More recently, we found that the effective component of bee venom is PLA2. Thus, we hypothesized that PLA2 could protect against liver injury induced by acetaminophen. To evaluate the hepatoprotective effects of PLA2, C57BL/6 mice or interleukin-10-deficient (IL-10−/−) mice were injected with PLA2 once a day for five days and sacrificed 24 h (h) after acetaminophen injection. The blood sera were collected 0, 6, and 24 h after acetaminophen injection for the analysis of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). PLA2-injected mice showed reduced levels of serum AST, ALT, proinflammatory cytokines, and nitric oxide (NO) compared with the PBS-injected control mice. However, IL-10 was significantly increased in the PLA2-injected mice. These hepatic protective effects were abolished in Treg-depleted mice by antibody treatment and in IL-10−/− mice. Based on these findings, it can be concluded that the protective effects of PLA2 against acetaminophen-induced hepatotoxicity can be mediated by modulating the Treg and IL-10 production.

Analgesic Effects of Bee Venom Derived Phospholipase A2 in a Mouse Model of Oxaliplatin-Induced Neuropathic Pain

“…However, our previous study has shown that BV has a beneficial role in reliving oxaliplatin-induced neuropathic pain symptoms in rats, suggesting that BV could be an alternative therapeutic option for the management of oxaliplatin-induced peripheral neuropathy [ 9 , 16 ]. Interestingly, we recently found that bvPLA 2 mitigates cisplatin-induced nephrotoxicity and acetaminophen-induced hepatotoxicity, which was more potent than BV [ 24 , 38 ]. In the present study, we investigated for the first time whether bvPLA 2 has an analgesic effect on oxaliplain-induced cold and mechanical allodynia.…”

“…The major pathway of the bvPLA 2 -induced immune modulation is to increase peripheral regulatory T cells, which play a key role in the maintenance of tolerance in the immune system. Our recent studies showed that such strategies using bvPLA 2 could be successful in the prevention of cisplatin-induced acute kidney and acetaminophen-induced acute liver injury, by suppressing immune response via the modulation of regulatory T cells [ 24 , 38 ]. Another previous study also demonstrated that regulatory T cells attenuate peripheral nerve injury-induced neuropathic pain in rats [ 49 ].…”

“…BV (1 mg/kg, i.p., Sigma) or bvPLA 2 (0.2 mg/kg, i.p., Sigma) [ 9 , 24 , 38 ] dissolved in phosphate buffered saline (PBS) was injected in oxaliplatin-administered mice for a continuous five days. Cold and mechanical sensitivity were measured by acetone test and von Frey hair test, respectively, before each bvPLA 2 or BV treatment.…”

Bee Venom Phospholipase A2: Yesterday’s Enemy Becomes Today’s Friend

“…Bee venom group III sPLA 2 can exert protective effects on airway inflammation via Treg cells in the mouse model of asthma [ 77 ]. Anti-inflammatory effects of bee venom group III sPLA 2 have been demonstrated in cisplatin-induced renal injury and acetaminophen-induced liver injury [ 59 , 78 ]. These protective effects of bee venom group III sPLA 2 against drug-induced organ toxicity are mediated by IL-10 production and Treg cell modulation.…”

The Protective Effect of Bee Venom on Fibrosis Causing Inflammatory Diseases

“…Kim et al demonstrated that PLA2 protects against hepatic dysfunction and induces anti-inflammatory cytokine production in acetaminophen-injected mice. This study suggests that PLA2 may have therapeutic potential in preventing acetaminophen-induced hepatotoxicity [ 60 ].…”