IFN-gamma represses epsilon germline transcription and subsequently down-regulates switch recombination to epsilon.
Cytokines have the ability to regulate the isotypes of antibodies produced during an immune response. For instance, IL-4 has been shown to induce the production of IgE by B cells, while IFN-gamma has been shown to inhibit this induction. Recent work has revealed that IL-4 appears to induce class switching to epsilon through its ability to specifically induce germline epsilon transcripts. Germline epsilon transcription appears to target class-switch recombination to the epsilon locus. However, the mechanism by which IFN-gamma inhibits the IL-4 induction of IgE is unknown. We hypothesized that IFN-gamma and IL-4 may have antagonistic effects on the same stage of B cell differentiation. Northern blotting analyses show that IFN-gamma suppresses the IL-4 induction of germline epsilon transcripts. In transient transfection assays, the IL-4 induction of transcription imparted by the minimal 179 bp germline epsilon promoter is repressed by IFN-gamma. Utilizing a digestion circularization-polymerase chain reaction assay we show that IL-4 induces switch recombination to epsilon, while IFN-gamma suppresses switch recombination to epsilon. These studies support a model that, through their differential effects on a cis-controlling element that regulates germline epsilon transcription, IL-4 and IFN-gamma are able to modulate B cell switch recombination to epsilon in a coordinated manner.
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032.
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D000818:Animals; D001402:B-Lymphocytes; D001483:Base Sequence; D002478:Cells, Cultured; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007073:Immunoglobulin E / Q000235:genetics*; D007371:Interferon-gamma / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D012045:Regulatory Sequences, Nucleic Acid; D013154:Spleen / Q000166:cytology; D014158:Transcription, Genetic / Q000502:physiology*
D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma