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Mechanisms of the action of adenine on anti-allergic effects in mast cells.

ABSTRACT: INTRODUCTION:Mast cells play an important role in allergic responses. METHODS:We herein demonstrated the mechanisms of inhibitory effect of adenine on IgE/antigen-induced degranulation and TNF-? release in mast cells. RESULTS:We found that these effects were dependent on the amino group of adenine because purine only weakly inhibited degranulation. Adenine also inhibited Ca2+ ionophore- and thapsigargin-induced degranulation, however, this inhibitory effect was weaker than that of the antigen. Therefore, the inhibitory effects of adenine on degranulation may be mediated before as well as after the Ca2+ raise under the antigen stimulus. Adenine inhibited antigen-induced Syk and the subsequent induction of AKT and ERK activation under Fc?RI-mediated signal. Adenine also attenuated antigen-induced increase in Ca2+ . Furthermore, adenine inhibited IgE/antigen-induced IKK?/? activation, which is involved in degranulation. Finally, adenine protected mice against anaphylactic allergic responses in vivo. CONCLUSIONS:The present study revealed a key role of adenine in the attenuation of allergic responses through the inhibition of Syk-mediated signal transduction and IKK-mediated degranulation.

SUBMITTER: Hosoi T

PROVIDER: S-EPMC5818451 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Mechanisms of the action of adenine on anti-allergic effects in mast cells.

Hosoi Toru T Ino Shinsuke S Ohnishi Fumie F Todoroki Kenichi K Yoshii Michiko M Kakimoto Mai M Müller Christa E CE Ozawa Koichiro K

Immunity, inflammation and disease 20171101 1

<h4>Introduction</h4>Mast cells play an important role in allergic responses.<h4>Methods</h4>We herein demonstrated the mechanisms of inhibitory effect of adenine on IgE/antigen-induced degranulation and TNF-α release in mast cells.<h4>Results</h4>We found that these effects were dependent on the amino group of adenine because purine only weakly inhibited degranulation. Adenine also inhibited Ca<sup>2+</sup> ionophore- and thapsigargin-induced degranulation, however, this inhibitory effect was w ...[more]

PMID: 29094492

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Project description:Atopic dermatitis is a chronic inflammatory skin disease that affects 15-30% of children and approximately 5% of adults in industrialized countries. Although the pathogenesis of atopic dermatitis is not fully understood, the disease is mediated by an abnormal immunoglobulin-E immune response in the setting of skin barrier dysfunction. Mast cells contribute to immunoglobulin-E-mediated allergic disorders including atopic dermatitis. Upon activation, mast cells release their membrane-bound cytosolic granules leading to the release of several molecules that are important in the pathogenesis of atopic dermatitis and host defence. More than 90% of patients with atopic dermatitis are colonized with Staphylococcus aureus in the lesional skin whereas most healthy individuals do not harbour the pathogen. Several staphylococcal exotoxins can act as superantigens and/or antigens in models of atopic dermatitis. However, the role of these staphylococcal exotoxins in disease pathogenesis remains unclear. Here we report that culture supernatants of S. aureus contain potent mast-cell degranulation activity. Biochemical analysis identified δ-toxin as the mast cell degranulation-inducing factor produced by S. aureus. Mast cell degranulation induced by δ-toxin depended on phosphoinositide 3-kinase and calcium (Ca(2+)) influx; however, unlike that mediated by immunoglobulin-E crosslinking, it did not require the spleen tyrosine kinase. In addition, immunoglobulin-E enhanced δ-toxin-induced mast cell degranulation in the absence of antigen. Furthermore, S. aureus isolates recovered from patients with atopic dermatitis produced large amounts of δ-toxin. Skin colonization with S. aureus, but not a mutant deficient in δ-toxin, promoted immunoglobulin-E and interleukin-4 production, as well as inflammatory skin disease. Furthermore, enhancement of immunoglobulin-E production and dermatitis by δ-toxin was abrogated in Kit(W-sh/W-sh) mast-cell-deficient mice and restored by mast cell reconstitution. These studies identify δ-toxin as a potent inducer of mast cell degranulation and suggest a mechanistic link between S. aureus colonization and allergic skin disease.

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Mechanisms of the action of adenine on anti-allergic effects in mast cells.

Publications

Mechanisms of the action of adenine on anti-allergic effects in mast cells.

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