INTERLEUKIN-5 (IL-5) PROVIDES A SIGNAL THAT IS REQUIRED IN ADDITION TO IL-4 FOR ISOTYPE SWITCHING TO IMMUNOGLOBULIN (IG) G1 AND IGE

We have examined the contributions of Interleukin 4 (IL-4), IL-5, and other stimuli to the expression of Immunoglobulin G1 (IgG1) and IgE in murine B lymphoblasts activated with anti-Ig. The combination of IL-4 and -5 induced B lymphoblasts to proliferate and to secrete IgM and IgG1. However, an additional stimulus was required along with IL-4 and -5 for induction of IgE secretion. This stimulus was provided by lipopolysaccharides (LPS) or cytokines produced by TC-1 or EL4 cells. In the absence of IL-5, exceptionally high concentrations of IL-4 (> 1,000 U/ml) were required to elicit IgG1 and IgE secretion from B lymphoblasts cultured with either LPS or TC-1-conditioned media (CM). To investigate regulation of expression of gamma-1 and epsilon-genes by IL-4, -5, and LPS, the requirements for induction of gamma-1 and epsilon-germline and productive transcripts were examined. Germline gamma-1, but not epsilon, transcripts were detected in RNA from B lymphoblasts treated with IL-4 and -5 for 48 h. In contrast, both germline gamma-1 and epsilon-transcripts could be detected in B lymphoblasts cultured with IL-4 and LPS, and steady state levels of germline gamma-1 transcripts were four- to sevenfold higher in blasts cultured with LPS and IL-4, compared with blasts cultured with IL-4 and -5. LPS enhanced steady state levels of germline transcripts induced by IL-4, but LPS did not promote substantial accumulation of productive gamma-1 and epsilon-transcripts. In contrast, IL-5 did not affect steady state levels of germline transcripts stimulated by IL-4, but did markedly increase levels of productive gamma-1 and epsilon-transcripts. Thus, lymphokines regulate two distinct events in isotype switching: induction of germline transcripts (IL-4), and production of VDJ-C-gamma-1 and VDJ-C-epsilon mRNA (IL-5), which leads to secretion of IgG1 and IgE.