Abstract
The mechanism underlying bee venom (BV) therapy is still controversial, with opinions ranging from constituent-based pharmacological action to homeopathic-like activity. The purpose of this study was to examine whether BV phospholipase A2 (bvPLA2), an enzymatic component of BV, is a novel anti-inflammatory and anti-arthritic mediator capable of stimulating CD25+ Foxp3+ regulatory T cell (Treg) polarization in a mouse model of human rheumatoid arthritis (RA). An experimental model of RA was established in male DBA/1 mouse by 2-week-interval injections of 100 μg type II collagen emulsified in complete (first injection) or incomplete Freund’s adjuvant (second injection) at the base of the tail. During arthritis development, bvPLA2 (0.1, 0.5, 1.0 mg/kg) and/or Treg inhibitors such as anti-CD25 antibodies and peptide 60 (P60) were injected intraperitoneally for 5 weeks. Arthritic symptoms and the expansion of Tregs were then assessed by behavioral assessments, histological and micro-CT imaging, and flow cytometry. bvPLA2 injections significantly alleviated arthritic behaviors such as squeaking and joint swelling, consistent with changes seen on both histological and micro-CT images. The anti-arthritic effects of bvPLA2 were blocked by intraperitoneal injections of 0.25 mg/kg anti-CD25 antibody and 10 μg/kg P60, as determined by behavioral assessments. Flow cytometric analysis of dendritic cells, B cells, and major T cell subsets from spleens revealed a significant depletion of Tregs following anti-CD25 antibody, but not P60, treatment. bvPLA2 treatment exerted significant anti-inflammatory and anti-arthritic activities in a mouse model of RA via the induction of Tregs.
Highlights
Honeybee venom is a bitter, colorless liquid containing a complex mixture of toxic peptides, enzymes, and bioactive amines secreted from the venom sacs of honeybees
The collagen-induced arthritis (CIA) mouse model was used to examine the anti-arthritic activity of BV phospholipase A2 (bvPLA2)
The squeaking score was significantly alleviated by i.p. injection of bvPLA2, which was started on day 18, in a dose-dependent manner
Summary
Honeybee venom is a bitter, colorless liquid containing a complex mixture of toxic peptides, enzymes, and bioactive amines secreted from the venom sacs of honeybees. Bee sting therapy has been used in traditional Chinese medicine for over 3000 years as a treatment for chronic pain and inflammation. Tregs are important for the maintenance of immune self-tolerance and homeostasis via downregulation of effector T cells[17] In this regard, any therapies capable of inducing the differentiation and expansion of Tregs may be effective for the treatment of autoimmune diseases such as rheumatoid arthritis (RA), psoriasis, type I diabetes, myasthenia gravis, multiple sclerosis, and systemic lupus e rythematosus[18,19,20,21,22,23,24,25,26]
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