Functional significance of IL-4 receptor on B cells in IL-4-induced human IgE production

Abstract

IL-4 with the IgE-inducing activity is shown to upregulate the expression of IL-4 receptor (IL-4R) on lymphocytes. Antisense strategy was used that aimed at investigating the significance of IL-4-induced upregulation of IL-4R on B cells in human IgE production. When an antisense phosphorothioate oligodeoxynucleotide to IL-4R (S-oligo 1) was added to B cells together with IL-4, the agent selectively abrogated the upregulation of IL-4R without affecting its constitutive level expression. Moreover, S-oligo 1 had a suppressive effect on the T-cell-independent synthesis of IgE by B cells costimulated with IL-4 and anti-CD40 antibody. This suppression was accompanied by inhibition of mature but not germline Ce transcription. These findings indicate that constitutively expressed IL-4R provides a signal or signals responsible for the induction of germline Cϵ transcription and suggest that IL-4R upregulation may be required for the subsequent class switch recombination that leads to mature Cϵ transcription and IgE synthesis. The IL-4R signal transduction mechanism underlying germline Cϵ transcription was also analyzed in a human Burkitt lymphoma B-cell line, DND39. Induction of germline Cϵ transcripts in DND39 cells by IL-4 required at least two distinct signaling cascades. One was mediated by enhancement of tyrosine phosphorylation of a 57 kd protein associated with phospholipase C-γ1 (PLC-γ1) that resulted in PLC-γ1 activation, inositol lipid hydrolysis, and protein kinase C δ translocation. The other was dependent on phosphatidylinositol 3-kinase, whose activation induced protein kinase C ζ translocation. In fact, kinase inhibitors such as herbimycin A, K-252a, and wortmannin were effective in inhibiting IL-4-induced germline Cϵ transcription. Therefore, in addition to activation of protein tyrosine kinases, coordinated actions of PLC-γ1 and phosphatidylinositol 3-kinase may be involved in IL-4-driven germline Cϵ transcription in DND39 cells. (J A LLERGY C LIN I MMUNOL 1995;96:1145-51.)