Mycoepoxydiene inhibits antigen-stimulated activation of mast cells and suppresses IgE-mediated anaphylaxis in mice

Highlights

• Mycoepoxydiene (MED) is a polyketide isolated from a marine fungus.

• MED inhibits degranulation and cytokine production in activated mast cells.

• MED suppresses IgE-mediated passive cutaneous anaphylaxis (PCA) in mice.

• MED suppresses mast cell activation and PCA through blocking Syk activation.

Abstract

Mycoepoxydiene (MED) is a polyketide isolated from a marine fungus associated with mangrove forest. It has been shown that MED has many kinds of effects such as anti-cancer and anti-inflammatory activities. However, its effects on anaphylaxis are still unknown. Mast cells play a pivotal role in IgE-mediated allergic response. Aggregation of the high affinity IgE receptor (FcεRI) on the surface of mast cell activates a cascade of signaling events leading to the degranulation and cytokine production in mast cells. Our study showed that MED could significantly suppress antigen-stimulated degranulation and cytokine production in mast cells and IgE-mediated passive cutaneous anaphylaxis (PCA) in mice. Furthermore, we found that MED suppressed antigen-induced activation of Syk, and subsequently inhibited the phosphorylation of PLCγ1, Akt, and MAPKs such as extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 in mast cells. Collectively, our study demonstrates that MED can inhibit the activation of mast cells and protect mice from mast cell-mediated allergic response through inhibiting the activation of Syk. These results suggest that MED is a potential compound for developing a promising anti-anaphylaxis drug.

Introduction

Anaphylaxis is a severe, systemic allergic reaction involving the respiratory and/or cardiovascular systems, usually with additional cutaneous and/or gastrointestinal features [1]. Anaphylaxis, especially food allergy, is a worldwide problem, with evidence of increasing prevalence in many countries. About 25% of people in developed countries suffer from allergy disorders which lead to heavy socioeconomic burden [2].

Immunoglobulin E antibodies and mast cells have been convincingly linked to the pathophysiology of anaphylaxis [3]. Mast cell progenitors in the bone marrow can be induced by interleukin-3 (IL-3) to proliferate and differentiate into bone marrow-derived mast cells (BMMCs). Several kinds of receptors are expressed on the surface of BMMCs among which high affinity receptor for IgE (FcεRI) is the most well-known one [4], [5]. Antigen-dependent activation of mast cells with specific IgE bound to their surface is the central event in anaphylaxis. The binding of antigen-specific IgE to FcεRI sensitizes mast cells and other effector cells to release mediators in response to subsequent encounter with specific antigens or crossreactive antigens [3]. Re-exposure to allergen can trigger the cross-linking of FcεRI aggregation on the surface of mast cell [6], [7]. Aggregation of FcεRI in turn activates Src family protein tyrosine kinases Lyn and Fyn [8], [9], [10]. This event leads to the stimulation of Syk through the phosphorylation of immune receptor tyrosine-based activation motif (ITAM) or through direct phosphorylation of Syk [8], [11]. Syk activation can stimulate several pathways including phospholipase (PL)Cγ, PI3K/Akt, and mitogen-activated protein kinases (MAPKs), leading to mast cell degranulation and production of cytokines and lipid mediators [12], [13]. Thus, mast cells exert a significant effect on allergic inflammation and provide a therapeutic target in the treatment of allergic diseases [2], [14].

Mycoepoxydiene (MED) is a novel polyketide isolated from the marine fungus Diaporhte sp. (D. sp.) HLY-1 found in submerged rotten leaves of Kandelia candel in a mangrove forest in Fujian Province, China [15]. Previous studies have shown that MED had anti-microbial and anti-cancer activities [15], [16]. Recently, we have demonstrated that MED could inhibit LPS-induced inflammatory responses and ovariectomy-induced osteoporosis in mice [17], [18]. In macrophages, MED significantly inhibits LPS-induced expression of pro-inflammatory mediators such as tumor necrosis factor α (TNF-α), IL-1β, IL-6, and nitric oxide (NO) through blocking the activation of both NF-κB and MAPK pathways [19]. As MED displays an anti-inflammatory function, we wonder whether it can suppress allergic response which also shows the activation of NF-κB and MAPK pathways [8]. In this study, we demonstrated that MED could inhibit the degranulation and cytokine production in antigen-stimulated mast cells through blocking the activation of Syk. In addition, MED effectively alleviated antigen-induced passive cutaneous anaphylaxis (PCA) in mice.