Bee Venom Phospholipase A2 Induces Regulatory T Cell Populations by Suppressing Apoptotic Signaling Pathway

Abstract

Bee venom phospholipase A2 is a lipolytic enzyme in bee venom that catalyzes hydrolysis of the sn-2 ester bond of membrane phospholipids to produce free fatty acid and lysophospholipids. Current evidence suggests that bee venom phospholipase A2 (bvPLA2) induces regulatory T cell expansion and attenuates several immune system-related diseases, including Alzheimer’s disease. The induction of Treg cells is directly mediated by binding to mannose receptors on dendritic cells. This interaction induces the PGE2-EP2 signaling pathway, which promotes Treg induction in CD4+ T cells. In this study, we investigated the effects of bvPLA2 treatment on the apoptotic signaling pathway in Treg populations. Flow cytometry was performed to identify early apoptotic cells. As a result, early apoptotic cells were dramatically decreased in bvPLA2-treated splenocytes, whereas rapamycin-treated cells showed levels of apoptotic cells similar to those of PBS-treated cells. Furthermore, bvPLA2 treatment increased expression of anti-apoptotic molecules including CTLA-4 and PD-1. The survival rate increased in bvPLA2-treated Tregs. Our findings indicate that bvPLA2-mediated modulation of apoptotic signaling is strongly associated with the Treg induction, which exhibits protective effects against various immune-related diseases. To our knowledge, this study is the first to demonstrate that bvPLA2 is the major bee venom (BV) compound capable of inducing Treg expansion through altering apoptotic signal.

Bee Venom: An Updating Review of Its Bioactive Molecules and Its Health Applications

“…This ability proposes bPLA2 as an alternative treatment for neuroinflammatory diseases as they mediate antiinflammatory effects [111,115]. A representation of this regulated expression pathway is shown in Figure 4 [111,116]. This Treg expression has been demonstrated to modulate apoptotic signalling and therefore, it possesses immunomodulatory properties [116].…”

“…A representation of this regulated expression pathway is shown in Figure 4 [111,116]. This Treg expression has been demonstrated to modulate apoptotic signalling and therefore, it possesses immunomodulatory properties [116]. Meanwhile, bPLA2 can induce a T helper type-2 (Th2) response that is dependent on MyD88 expression in T cells, inducing an immune protective response against future BV exposure [117].…”

Clinical Applications of Bee Venom Acupoint Injection

“…PLA2 can bind to cluster of differentiation 206 (CD206), a dendritic cells (DC) surface receptor, and stimulate the secretion of prostaglandin E2 (PGE2). When PGE2 binds to prostaglandin E2 receptor 2 (EP2), forkhead box P3 (Foxp3) will increased expression, causing naïve T helper cells to differentiate into CD4 + CD25 + Foxp3 + Treg cells [ 35 , 36 , 37 ]. Moreover, research showed the portion of resting Treg cell (CD62LhiCD127low) has increased with bvPLA2 treatment [ 36 ].…”

“…When PGE2 binds to prostaglandin E2 receptor 2 (EP2), forkhead box P3 (Foxp3) will increased expression, causing naïve T helper cells to differentiate into CD4 + CD25 + Foxp3 + Treg cells [ 35 , 36 , 37 ]. Moreover, research showed the portion of resting Treg cell (CD62LhiCD127low) has increased with bvPLA2 treatment [ 36 ]. Ye et al [ 38 ] suggested that bvPLA2 has a neuroprotective effect through microglial deactivation as well as reduction in CD4 + T cell infiltration.…”

Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics

“…A total of 11 studies were published. Three reviews provided a good overview of the therapeutic effect of bee venom [ 6 , 7 , 8 ], and eight original research articles focused on bee venom, melittin, PLA 2 , and apamin [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”