Abstract
Mast cells are immune cells critical in the pathogenesis of allergic, but also inflammatory and autoimmune diseases through release of many pro-inflammatory cytokines such as IL-8 and TNF. Contact dermatitis and photosensitivity are skin conditions that involve non-immune triggers such as substance P (SP), and do not respond to conventional treatment. Inhibition of mast cell cytokine release could be effective therapy for such diseases. Unfortunately, disodium cromoglycate (cromolyn), the only compound marketed as a mast cell “stabilizer”, is not particularly effective in blocking human mast cells. Instead, flavonoids are potent anti-oxidant and anti-inflammatory compounds with mast cell inhibitory actions. Here, we first compared the flavonoid quercetin (Que) and cromolyn on cultured human mast cells. Que and cromolyn (100 µM) can effectively inhibit secretion of histamine and PGD2. Que and cromolyn also inhibit histamine, leukotrienes and PGD2 from primary human cord blood-derived cultured mast cells (hCBMCs) stimulated by IgE/Anti-IgE. However, Que is more effective than cromolyn in inhibiting IL-8 and TNF release from LAD2 mast cells stimulated by SP. Moreover, Que reduces IL-6 release from hCBMCs in a dose-dependent manner. Que inhibits cytosolic calcium level increase and NF-kappa B activation. Interestingly, Que is effective prophylactically, while cromolyn must be added together with the trigger or it rapidly loses its effect. In two pilot, open-label, clinical trials, Que significantly decreased contact dermatitis and photosensitivity, skin conditions that do not respond to conventional treatment. In summary, Que is a promising candidate as an effective mast cell inhibitor for allergic and inflammatory diseases, especially in formulations that permit more sufficient oral absorption.
Highlights
Mast cells derive from hematopoietic progenitors and mature in tissues depending on microenvironmental conditions [1,2]
Stimulation of human umbilical cord blood-derived cultured mast cells (hCBMCs) with IgE/Anti-IgE results in rapid secretion of large amounts of histamine, PDG2 and LTs (Fig. 1A–C)
We report on the comparative inhibitory effect of WSQ, Que and the ‘‘mast cell stabilizer’’ cromolyn on human mast cell secretion of inflammatory mediators
Summary
Mast cells derive from hematopoietic progenitors and mature in tissues depending on microenvironmental conditions [1,2]. Mast cells are important effector cells in allergic reactions [3,4,5,6] by secreting histamine, leukotrienes (LTs), prostaglandin D2 (PGD2), proteolytic enzymes and several multifunctional cytokines, such as interleukin-6 (IL-6), IL-8, IL-13, tumor necrosis factor (TNF), and vascular endothelial growth factor (VEGF) [7,8,9]. These mediators contribute to the late-phase reactions and to inflammation through the recruitment and activation of immune cells [10,11]. Mast cells were shown to be involved in contact dermatitis in mice [19,20]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.