Structure and expression of murine germ-line immunoglobulin epsilon heavy chain transcripts induced by interleukin 4.

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Abstract
The murine lymphokine, interleukin 4 (IL-4) is able to specifically promote isotype switching to IgG1 and IgE in cultures of mitogen-stimulated B cells. Emerging evidence suggests that germ-line immunoglobulin heavy chain gene transcription may direct switching by modulating switch-region accessibility to a recombinase. In this study, cloned cDNA copies of the germ-line .epsilon. heavy chain transcript have been used to determine the genomic organization of this transcription unit. The 5'' end of these transcripts are derived from an exon, denoted I.epsilon., located 2 kilobases 5'' of the C.epsilon. switch region [C.epsilon. = .epsilon. heavy chain constant (C) region gene]. Nucleotide sequence analysis reveals that this RNA does not encode a protein, as the I.epsilon. exon contains termination codons in all reading frames. Germ-line .epsilon. chain transcripts can be detected in cultures of normal splenic B cells treated with IL-4 within 24 hr, and this expression correlates with subsequent switching to C.epsilon.. Consistent with the IL-4 inducibility of this RNA is the identification of a motif upstream from the site of transciption initiation that closely resembles a transcription element implicated in the IL-4 regulation of the gene encoding the murine class II histocompatibility antigen, A.alpha.k. These data lend support to the accessibility model of isotype switching and implicate IL-4 in the transcriptional activation of the C.epsilon. locus.