Monomeric IgE stimulates NFAT translocation into the nucleus, a rise in cytosol Ca2+, degranulation, and membrane ruffling in the cultured rat basophilic leukemia-2H3 mast cell line.
Mast cells are key regulators in allergy and inflammation, and release histamine, cytokines, and other proinflammatory mediators. In the classical view, IgE acts merely to prime mast cells, attaching to FcepsilonRs but not evoking any cell signaling response until cross-linked by the presence of a multivalent allergen. However, several recent studies have reported that IgE alone can promote cell survival and cytokine production in the absence of cross-linking by allergen. In this study we demonstrate that acute addition of monomeric IgE elicits a wide spectrum of responses in the rat basophilic leukemia-2H3 mast cell line, including activation of phospholipases Cgamma and D, a rise in cytosol Ca(2+), NFAT translocation, degranulation, and membrane ruffling within minutes. Calcium transients persist for hours as long as IgE is present resulting in the maintained translocation of the transcription factor NFAT to the nucleus. Removal of IgE reverses the signaling processes. Our results indicate that, far from simply preparing the cells for a response to allergen, monomeric IgE can stimulate signaling pathways that lead to degranulation, membrane ruffling, and NFAT translocation. The mechanism of activation is likely to be via aggregation of the FcepsilonR1 because activation by IgE can be inhibited with monovalent hapten.
Pandey
Vinita
V
Department of Physiology, University College London, London, United Kingdom.
Mihara
Shoji
S
Fensome-Green
Amanda
A
Bolsover
Stephen
S
Cockcroft
Shamshad
S
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000276:immunology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D007073:Immunoglobulin E / Q000302:isolation & purification / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007946:Leukemia, Mast-Cell / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010739:Phospholipase D / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism*; D000077191:Wortmannin
D000730:Androstadienes; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D007073:Immunoglobulin E; D010739:Phospholipase D; D002118:Calcium; D000077191:Wortmannin