Biochemical and Biophysical Research Communications
Molecular hydrogen suppresses FcεRI-mediated signal transduction and prevents degranulation of mast cells
Introduction
Type I allergy or immediate-type hypersensitivity is involved in a variety of allergic diseases such as bronchial asthma, rhinitis, conjunctivitis, pollinosis, and urticaria. Mast cells are key effector cells in immunoglobulin E (IgE)-mediated immune responses including type I allergic reaction. High-affinity IgE receptor, FcεRI, expressed on the surface of mast cells is a heterotetrameric receptor composed of an IgE-binding α-subunit, β-subunit, and two γ-subunits [1]. When antigens react with IgE molecules bound to FcεRI, aggregation of receptors and activation of signal transduction pathways take place, resulting in degranulation and release of preformed mediators, production of cytokines, and secretion of leukotriens [2].
In these two years, molecular hydrogen has been shown to exert beneficial effects in animal models of a number of oxidative stress-associated diseases. Inhalation of hydrogen gas is protective against cerebral infarction [3], hepatic ischemia/reperfusion injury [4], myocardial ischemia/reperfusion injury [5], neonatal hypoxic brain injury [6], and small intestinal transplantation-induced inflammation [7]. Similarly, oral intake of hydrogen-rich water is beneficial in stress-induced learning impairment [8], atherosclerosis [9], Parkinson’s disease [10], and inflammatory bowel disease [11]. In humans, oral intake of hydrogen-rich water improves lipid and glucose metabolism in patients with diabetes and impaired glucose tolerance [12]. Based on the observations that hydrogen exclusively scavenges hydroxyl radical [3], [13], hydrogen effects in oxidative stress-associated diseases have been solely ascribed to the reduction of oxidative stress [3], [4], [5], [6], [7], [8], [9], [10], [11], [12].
Immediate-type allergy is, however, not causally associated with oxidative stress, and effects of hydrogen have not been reported to date. In the present study, we first demonstrated preventive effects of oral intake of hydrogen-rich water on type I allergic reaction in a mouse model. Using a mast cell culture model, we then elucidated that hydrogen attenuates degranulation through suppression of the FcεRI-mediated signal transduction. Effects of molecular hydrogen on signal transduction have not been documented to date. We propose that modulations of signaling pathways are essential underlying mechanisms of molecular hydrogen on a broad spectrum of diseases.
Section snippets
Materials and methods
Antibodies. Anti-dinitrophenol (DNP) IgE was from Yamasa (Tokyo, Japan). The antibodies to Akt, p-Akt, p44/42 MAP kinase (ERK1/2), p-p44/42 MAP kinase (Thr202/Tyr204), SAPK/JNK (JNK), p-SAPK/JNK (Thr183/Tyr185), p38 MAP kinase (p38), p-p38 MAP kinase (Thr180/Tyr182), Lyn, p-Lyn, cPLA2, p-cPLA2, p-PLCγ1, p-PLCγ2, and p-Syk were from Cell Signaling Technology (Beverly, CA). The antibodies against Syk, p22phox, p40phox, p47phox, p67phox, gp91phox, and Rac were from Santa Cruz Biotechnology (Santa
Oral intake of hydrogen-rich water attenuates PCA reaction in ICR mice
PCA is an animal model of immediate-type allergic reaction, which has been widely used to evaluate effects of anti-allergic drugs [14]. We first examined effects of hydrogen on PCA reaction. ICR mice were fed with either hydrogen-rich or control water for 2 or 4 weeks followed by PCA assays. In mice treated with hydrogen-rich water, leakage of Evans blue dye from circulation to skin was efficiently abolished (Fig. 1A). As shown in Fig. 1B, pretreatment with hydrogen-rich water for 2 and 4 weeks
Discussion
We demonstrated preventive effects of oral intake of hydrogen-rich water on type I allergic reaction in a mouse model and elucidated molecular mechanisms underlying the hydrogen effects. Hydrogen attenuated type I allergy in mice through suppression of the FcεRI-mediated signal transduction. Our studies suggest that hydrogen may be effective for a wide variety of allergic diseases such as bronchial asthma, rhinitis, conjunctivitis, pollinosis, and urticaria in humans. However, before making a
Competing interest statement
The authors declare no conflict of interest.
Acknowledgments
We thank Blue Mercury Inc. (Tokyo, Japan) and Dr. J. Rivera (NIH, Bethesda, MD) for providing us with hydrogen-rich water and anti-FcεRIβ antibody, respectively. This work was supported by Grant for Biological Research from Gifu prefecture, Japan and Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.
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