Abstract
Eosinophils are potent pro-inflammatory cells. Not only in allergic diseases but also in other diseases there is a need for treatment strategies to induce resolution of eosinophil-mediated inflammation. During the last years beneficial non-antibiotic activities of tetracyclines (TCNs) have been shown in different diseases in which eosinophils play a role, for example, asthma and bullous pemphigoid. The working mechanism of these effects remains to be clarified. Aim of the present study was to investigate the effects of TCNs on eosinophils. Flow cytometry analysis of apoptosis, mitochondrial membrane potential, activation of caspases, intracellular H2O2 and calcium, surface expression of eosinophil activation markers was performed in highly purified peripheral blood eosinophils of non-atopic donors. Tetracycline hydrochloride, minocycline and doxycycline significantly induced eosinophil apoptosis. All TCNs were able to significantly overcome the strong survival enhancing effects of pro-eosinophilic cytokines and staphylococcus aureus enterotoxins. Tetracycline hydrochloride induced eosinophil apoptosis was accompanied by intracellular production of hydrogen peroxide, loss of mitochondrial membrane potential and activation of caspases. Moreover, tetracycline hydrochloride significantly down regulated eosinophil surface expression of CD9 and CD45, and of the activation markers CD11b and CD69, but not of CD54, CD63, or CD95. Our data, propably for the first time, point to a potent anti-inflammatory role of TCNs on eosinophils.
Highlights
TCNs Induced Caspase-Dependent Eosinophil Apoptosis Preceded by Mitochondrial Damage
As tetracycline hydrochloride induced fewest necrotic eosinophils and significantly and dose-dependently induced apoptosis, we chose this TCNs for further experiments
Stimulation with tetracycline hydrochloride at 5 × 10−4 M resulted in a significant loss of mitochondrial membrane potential ( m; p = 0.005 compared to medium, n = 5, Figure 3A)
Summary
Eosinophils are multifunctional leukocytes and by modulating innate and adaptive immunity, they play a pro-inflammatory key role in several diseases [1] including parasitic infections [2] allergic diseases such as atopic dermatitis and inhalant allergy [3,4,5,6,7], and autoimmune diseases such as bullous pemphigoid [8], esophageal [9], and gastrointestinal disorders [10], mental disorders [11] and cancer [12,13,14]. Only few promoters of eosinophil apoptosis aside from glucocorticosteroids [15, 16] have been described, for example, theophylline [17] transforming growth factor-ß [18, 19], abrogation of Fas/CD95 by its ligand or a monoclonal antibody (mAb) [20, 21] or CD69 perturbation with mAb [22] Most of these are not available as prescription drugs or have potent adverse effects. Several studies have conclusively reported non-antibiotic activities of TCNs including anti-inflammatory, immunemodulating and neuroprotective properties and many clinical trials are ongoing over a wide range of diseases including dermatological diseases, behavior and mental disorders, immune system disorders, cardiovascular diseases, and cancer [25]. The prominent deleterious role of eosinophils in bullous pemphigoid is well-established [28,29,30,31]
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