Abstract
BackgroundActivator protein-1 (AP1), a c-Fos–JUN transcription factor complex, mediates many cytobiological processes. c-Fos has been implicated in immunoglobulin (Ig)E activation of mast cells (MCs) via high-affinity IgE Fc receptor (FcεRI) binding. This study examined c-Fos involvement in MC activation and tested the effects of the c-Fos/AP1 inhibitor T-5224 on MCs activation and allergic responses.MethodsIn vitro studies were conducted with two MC model systems: rat basophilic leukemia cells (RBLs) and mouse bone marrow derived mast cells (BMMCs). MC degranulation and effector functions were examined with β-hexosaminidase release and cytokine secretion assays. c-Fos/AP1 was inhibited with T-5224. c-Fos activity was suppressed with short hairpin RNA targeting c-Fos (shFos). In vivo immune responses were evaluated in passive cutaneous anaphylaxis (PCA) and ovalbumin-induced active systemic anaphylaxis (ASA) models, as well as in an oxazolone (OXA)-induced model of atopic dermatitis, a common allergic disease.Resultsc-Fos expression was elevated transcriptionally and translationally in IgE-stimulated MCs. c-Fos binding of the Egr1 (early growth response 1) promoter upregulated Egr1 transcription, leading to production of interleukin (IL)4. T-5224 reduced FcεRI-mediated MC degranulation (evidenced by β-hexosaminidase activity and histamine levels) and diminished EGR1 and IL4 expression. T-5224 attenuated IgE-mediated allergic responses in PCA and ASA models, and it suppressed MC-mediated atopic dermatitis in mice.ConclusionIgE binding can activate MCs via a c-Fos/Egr1/IL-4 axis. T-5224 suppresses MC activation in vitro and in vivo and thus represents a promising potential strategy for targeting MC activation to treat allergic diseases.
Highlights
Allergic diseases are disruptive to quality of life, can cause serious morbidity, and their incidence has been on the rise [1]
FcεRIstimulated mast cells (MCs) activation and anaphylaxis were shown to be dampened by antagonism of an orphan nuclear receptor called nuclear receptor subfamily 4 group A member 1, which acts in opposition to the antiinflammatory liver kinase B1/adenosine monophosphate-activated protein kinase axis [11]
We identified MC activation-associated proteins that interact with c-Fos, including early growth response (EGR), IL, and chemokine (C–C motif ) ligand (CCL) proteins [19, 20]
Summary
Allergic diseases are disruptive to quality of life, can cause serious morbidity, and their incidence has been on the rise [1]. Mast cells (MCs) play a key role in immunoglobulin (Ig)E mediated allergic reactions [2]. Binding of high-affinity IgE Fc receptors (FcεRIs) on the surface of MCs by antigen (Ag)-linked IgE antibodies activates the IgE/FcεRI pathway, which promotes cellular degranulation and the release of. Activator protein-1 (AP1), a c-Fos–JUN transcription factor complex, mediates many cytobiological processes. C-Fos has been implicated in immunoglobulin (Ig)E activation of mast cells (MCs) via high-affinity IgE Fc receptor (FcεRI) binding. This study examined c-Fos involvement in MC activation and tested the effects of the c-Fos/ AP1 inhibitor T-5224 on MCs activation and allergic responses
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