Activation of human mast cells through the platelet-activating factor receptor

• Published in: Journal of allergy and clinical immunology Vol. 125; no. 5; pp. 1137 - 1145.e6
• Main Authors: Kajiwara, Naoki, Sasaki, Tomomi, Bradding, Peter, Cruse, Glenn, Sagara, Hironori, Ohmori, Kazumitsu, Saito, Hirohisa, Ra, Chisei, Okayama, Yoshimichi
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.05.2010; Elsevier; Elsevier Limited
• Subjects: Allergies; Allergy and Immunology; Anaphylaxis; Anaphylaxis - immunology; Anaphylaxis - physiopathology; Biological and medical sciences; Cells, Cultured; Cytokines; Experiments; Fundamental and applied biological sciences. Psychology; Fundamental immunology; histamine; Histamine Release; human lung mast cells; human peripheral blood–derived mast cells; human skin mast cells; Humans; Immunopathology; Kinases; Ligands; Lung - cytology; Mast Cells - cytology; Mast Cells - immunology; Mast Cells - metabolism; Medical sciences; Platelet Activating Factor - metabolism; Platelet Membrane Glycoproteins - metabolism; platelet-activating factor receptor; Proteins; Receptors, G-Protein-Coupled - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Signal Transduction; Skin - cytology; Statistical analysis; histamine; platelet-activating factor receptor; PLC; human skin mast cells; PKC; human lung mast cells; IMDM; PB; Anaphylaxis; PAF; PTX; shRNA; MC; PG; human peripheral blood–derived mast cells; GPCR; PAI-1; GAPDH; MRGX2; PAF-R; Protein kinase C; Platelet-activating factor; Pertussis toxin; Plasminogen activator inhibitor 1; Mas-related G protein–coupled receptor family member X2; Peripheral blood; Prostaglandin; Phospholipase C; Glyceraldehyde-3-phosphate dehydrogenase; G protein–coupled receptor; Mast cell; Iscove modified Dulbecco medium; Short hairpin RNA; Human; Allergy; Immunopathology; Lung; Activation; Respiratory system; human peripheral blood-derived mast cells; Platelet-activating factor receptor; Histamine; Blood cell; Immunology; Skin
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2010.01.056

In human subjects platelet-activating factor (PAF) concentrations are markedly increased in the plasma after anaphylactic reactions, and these correlate strongly with the severity of the response. The mechanism for the systemic spread of mast cell (MC) activation in anaphylaxis is often assumed to relate to the hematogenous spread of allergen, but this is implausible, and amplification mechanisms need to be considered. We have investigated the ability of PAF to induce human MC degranulation using skin, lung, and peripheral blood (PB)–derived cultured MCs and the signaling pathways activated in PB-derived MCs in response to PAF. The expression of PAF receptor was investigated by means of RT-PCR and Western blot analysis. Cell-signaling pathways in PB-derived MCs in response to PAF were investigated by analyzing the effect of various inhibitors and the silencing of phospholipase C (PLC) mRNA on PAF-mediated histamine release. We show for the first time that PAF induces histamine release from human lung MCs and PB-derived MCs but not skin MCs. Activation of PAF receptor–coupled G αi leads to degranulation through PLCγ1 and PLCβ2 activation in human MCs. PAF-induced degranulation was rapid, being maximal at 5 seconds, and was partially dependent on extracellular Ca 2+. Our findings provide a mechanism whereby PAF mediates an amplification loop for MC activation in the generation of anaphylaxis.