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.