A 19-year-old woman comes to the office to discuss treatment options for seasonal sneezing, rhinorrhea, and nasal congestion. She has had these symptoms for the past few springs and summers but is now willing to "try anything" to allow her to concentrate on her upcoming final exams. The patient has no significant medical history, takes no medications, and has no drug allergies. Vital signs are within normal limits and physical examination reveals mild bilateral pale and boggy nasal turbinates with copious clear mucus. Fluticasone, an intranasal glucocorticoid, is prescribed. Which of the following is the most likely mechanism of action of this drug?
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This patient with allergic rhinitis has been prescribed fluticasone, an intranasal glucocorticoid.
Glucocorticoids bind to cytoplasmic receptors and translocate to the nucleus where they inhibit transcription of genes that encode inflammatory mediators and decrease immune cell survival and propagation. This results in wide-ranging effects that suppress immunostimulatory activity of all leukocyte cell lines, including the following:
Decreased tissue production of proinflammatory prostaglandins and leukotrienes through the inhibition of phospholipase A2
Decreased synthesis of almost all proinflammatory cytokines, with increased anti-inflammatory cytokine (eg, IL-10) production
Impaired macrophage activation and neutrophil emigration
Increased apoptosis of eosinophils, T cells, and monocytes, perhaps by decreasing Bcl-2 expression
Glucocorticoids also act on nonimmune cells in the nose (including epithelial cells, goblet cells, and vascular endothelial cells) to decrease uptake of allergen particles, decrease mucus production, and decrease vascular permeability.
(Choice B) Mast cells and eosinophils release cysteinyl-containing leukotrienes (leukotriene C4, D4, and E4) that trigger mucus secretion and edema. Cysteinyl leukotriene receptor antagonists (eg, montelukast, zafirlukast) block these leukotriene-mediated effects to improve symptoms of allergic rhinitis.
(Choice C) The anti-IgE antibody omalizumab binds circulating IgE to decrease serum IgE levels and limit the allergen-induced immunologic response.
(Choice D) In addition to inducing T cell apoptosis, glucocorticoids also promote (not reduce) differentiation of T cells into regulatory subsets. These regulatory T cells (Treg) decrease the immune response to allergens partly by producing IL-10, which inhibits macrophage function and downregulates expression of major histocompatibility complex (MHC) class II on antigen-presenting cells.
Educational objective:
Glucocorticoids inhibit transcription of proinflammatory mediators and promote apoptosis of eosinophils, T cells, and monocytes.