title: Control of the STAT6-BCL6 antagonism by SWAP-70 determines IgE production.
abstract: Asthma and allergies are major health concerns in which Ig isotype E plays a pivotal role. Ag-bound IgE drives mast cells and basophils into exocytosis, thereby promoting allergic and potentially anaphylactic reactions. The importance of tightly regulated IgE production is underscored by severe immunological conditions in humans with elevated IgE levels. Cytokines direct IgH class-switching to a particular isotype by initiation of germline transcription (GLT) from isotype-specific intronic (I) promoters. The switch to IgE depends on IL-4, which stimulates GLT of the Iε promoter, but is specifically and strongly impaired in Swap-70(-/-) mice. Although early events in IL-4 signal transduction (i.e., activation of the JAK/STAT6 pathway) do not require SWAP-70, SWAP-70 deficiency results in impaired Iε GLT. The affinity of STAT6 to chromatin is reduced in absence of SWAP-70. Chromatin immunoprecipitation revealed that SWAP-70 binds to Iε and is required for association of STAT6 with Iε. BCL6, known to antagonize STAT6 particularly at Iε, is increased on Iε in absence of SWAP-70. Other promoters bound by BCL6 and STAT6 were found unaffected. We conclude that SWAP-70 controls IgE production through regulation of the antagonistic STAT6 and BCL6 occupancy of Iε. The identification of this mechanism opens new avenues to inhibit allergic reactions triggered by IgE.
authors.affiliation: Institute of Physiological Chemistry, Faculty of Medicine Carl Gustav Carus, Dresden University of Technology, 01307 Dresden, Germany.
authors.forename: Tatsiana
authors.initials: T
authors.lastname: Audzevich
authors.forename: Glen
authors.initials: G
authors.lastname: Pearce
authors.forename: Michael
authors.initials: M
authors.lastname: Breucha
authors.forename: Gamze
authors.initials: G
authors.lastname: Günal
authors.forename: Rolf
authors.initials: R
authors.lastname: Jessberger
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006967:Hypersensitivity / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology*; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007143:Immunoglobulin Heavy Chains / Q000276:immunology; D007139:Immunoglobulin epsilon-Chains / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051560:Proto-Oncogene Proteins c-bcl-6; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D014158:Transcription, Genetic
chemical_list: C490010:Bcl6 protein, mouse; D002843:Chromatin; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D007143:Immunoglobulin Heavy Chains; D007139:Immunoglobulin epsilon-Chains; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; C113365:Swap70 protein, mouse; D015847:Interleukin-4; D007073:Immunoglobulin E