Role of protein kinase A in the inhibition of human mast cell histamine release by β-adrenergic receptor agonists

Abstract

Background: Although β‐adrenergic receptor agonists inhibit antigen‐induced release of histamine, leukotrienes and prostaglandin D2 from human lung fragments, dispersed human lung mast cells and human skin mast cells, subcellular mechanisms for the inhibition of histamine release by β‐adrenergic receptor agonists are not well delineated. The aim of the present study was to investigate the inhibitory mechanisms of β‐adrenergic receptor agonists for human mast cell histamine release using human cultured mast cells. Methods: Human mast cells were obtained by culturing umbilical cord blood CD34+ cells in the presence of stem cell factor and interleukin‐6. Cultured mast cells were sensitized with human myeloma IgE and stimulated with antihuman IgE. Results: Stimulation of mast cells induced the elevation of intracellular cytosolic free Ca2+ concentrations ([Ca2+]i) and the translocation of protein kinase C (PKC) from the cytosol to the cell membrane, followed by the release of stored histamine. Isoproterenol, sal­butamol and dibutyryl cAMP inhibited both the histamine release and PKC translocation, whereas they failed to affect the elevation of [Ca2+]i. H‐89, a protein kinase A (PKA) inhibitor, abrogated the inhibition. Conclusions: The present results suggest that PKA activation induced by β‐adrenergic receptor agonists plays a crucial role in inhibiting IgE‐mediated histamine release from human cultured mast cells through suppressing PKC translocation.

Differential Effects of .BETA.2-Adrenoceptor Desensitization on the IgE-Dependent Release of Chemical Mediators from Cultured Human Mast Cells

“…[10][11][12][13] We also reported that b 2 -adrenoceptor agonists inhibit the chemical mediator release in cultured human mast cells. [14][15][16] b 2 -Adrenoceptor agonists inhibit mediator release from human mast cells far more potently than disodium cromoglycate. 6,8,13,14) Furthermore, b 2 -adrenoceptor agonists inhibit PGD 2 and LT release more potently than histamine release from human mast cells.…”

Case Report: Mast cell anergy: absence of symptoms after accidental re-exposure to amoxicillin/clavulanic acid 3 days after anaphylaxis

“…Studies have shown that β-adrenergic receptor agonists inhibit IgE-dependent histamine release by human mast cells ( 26 ) and that exposing healthy volunteers to salmeterol and terbutaline attenuates the cutaneous mast cell response for up to 24 h postexposure ( 27 ). However, it is not known whether these inhibitory effects follow a dose–response curve nor whether they are durable with molecules such as adrenaline, the first-line treatment for anaphylaxis and used in large quantities, as in our patient.…”

Mast Cell Anergy: absence of symptoms after accidental re-exposure to amoxicillin/clavulanic acid 3 days after anaphylaxis

“…20,21,22,23,24 The description of the change from positive to negative skin test in a patient allergic to carboplatin after desensitization provides evidence that mast cell inhibitory mechanisms do not need massive release of mediators. 25 Studies have shown that β-adrenergic receptor agonists inhibit IgE-dependent histamine release by human mast cells, 26 and that exposing healthy volunteers to salmeterol and terbutaline attenuates the cutaneous mast cell response for up to 24 hours post-exposure. 27 However, it is not known whether these inhibitory effects follow a dose-response curve, nor whether they are durable with molecules such as adrenaline, the first-line treatment for anaphylaxis and used in large quantities in our patient's case.…”