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  • br Conflict of interest statement br Introduction


    Conflict of interest statement
    Introduction Tanshinone IIA (Tan IIA) is a major active component of Salvia miltiorrhiza (S. miltiorrhiza), a well-known Chinese traditional medicine that is used for the treatment of cardiovascular and cerebrovascular diseases [1]. Tan IIA exhibits diverse pharmacologic effects, including anti-atherosclerotic, anti-inflammatory, anti-oxidant, anti-allergic, and neuroprotective properties [2], [3], [4], [5]. However, the mechanisms underlying its anti-allergic activity at the cellular and molecular levels have not been established. Mast Malotilate synthesis play a key role in allergic diseases and inflammatory disorders through the release of various chemical mediators. Aggregation of IgE bound FcεRI by cognate antigen (Ag) results in phosphorylation of the immunoreceptor tyrosine-based activating motif (ITAM) in the β and γ subunits of FcεRI via activated Src tyrosine kinases such as Lyn and Fyn. The phosphorylated ITAM serves as a docking site for the SH2 domain of Syk, leading to activation of this central tyrosine kinase. Syk activation results in the phosphorylation of several downstream signaling molecules, such as linker for activation of T cells (LAT) and phospholipase Cγ (PLCγ), which play crucial roles in intracellular Ca2+ release, degranulation, and generation of lipid mediators such as leukotriene C4 (LTC4) and prostaglandin D2 (PGD2). FcεRI signaling also leads to activation of mitogen-activated protein kinases (MAPKs) and the phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) and IκB kinase (IKK)-nuclear factor-κB (NF-κB) pathways, which play essential roles in the expression of an array of cytokines and chemokines [6], [7], [8]. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is crucial for the maintenance of cellular and whole body energy homeostasis [9], [10]. In general, AMPK is activated during energy insufficiency through a principal upstream kinase, liver kinase B1 (LKB1). Importantly, we recently reported that the LKB1-AMPK axis is a novel negative regulator of FcεRI signaling that is counter-regulated by Fyn and extracellular signal-regulated kinase (ERK) in mouse mast cells [11], [12]. Sirtuin1 (Sirt1), a NAD+-dependent type III histone/protein deacetylase, deacetylates various transcription factors, including peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator-1α (PGC-1α), forkhead transcription factors, p53, and NF-κB, that regulate energy metabolism, aging, cellular senescence, autophagy, apoptosis, and inflammation [13], [14], [15]. Growing bodies of evidence have revealed that Sirt1 cooperates with the LKB1-AMK pathway and that dysregulation of Sirt1 is associated with metabolic syndrome and inflammation [16], [17], [18], [19]. Although the role of Sirt1 in allergic diseases had been controversial [20], [21], [22], we recently demonstrated that Sirt1 suppresses mast cell activation mainly through activation of the LKB1-AMPK axis [23]. It was reported that Tan IIA improved endoplasmic reticulum (ER) stress-induced insulin resistance in L6 myotubes and reduced blood glucose levels and body weight in db/db mice through activation of AMPK [24]. This finding led us to hypothesize that the activation of AMPK might underlie the anti-allergic activity of Tan IIA. Indeed, in the present study, Tan IIA suppressed mast cell activation and anaphylaxis via activation of the Sirt1-LKB1-AMPK axis, providing a mechanistic insight into the anti-allergic activity of this natural product.
    Material and methods
    Discussion Tan IIA, a major component in the traditional Chinese natural medicine S. miltiorrhiza[27], improves myocardial ischemia injury [28], inhibits Tat-induced HIV-1 transactivation [29], and ameliorates ER stress-induced insulin resistance [24] through activation of the AMPK pathway. Although it was previously reported that tanshinones isolated from S. miltiorrhiza inhibited PCA, the underlying mechanism remained largely obscure [4]. In the present study, Tan IIA inhibited IgE/Ag-stimulated mast cell activation in vitro and mast cell-mediated anaphylaxis in vivo through activation of the Sirt1-LKB1-AMPK pathway. We recently reported that IgE/Ag-induced activation of mast cells is negatively regulated by the Sirt1-LKB1-AMPK pathway and suggested that agonists of this pathway might be useful for the treatment of allergic diseases [11], [23], or metabolic syndrome, as has been proposed [30], [31]. We now show, using mice with genetic deletions and siRNA knockdown of the Sirt1-LKB1-AMPK pathway, that Tan IIA activates Sirt1 and thereby LKB1-AMPK, which in turn dampens FcεRI signaling.