IL-4 activates a latent DNA-binding factor that binds a shared IFN-gamma and IL-4 response element present in the germ-line gamma 1 Ig promoter.

Abstract

IL-4 regulates transcription of the germ-line gamma 1 Ig gene in murine B cells and by doing so targets this isotype for switch recombination by an unknown mechanism. In this study, we have identified an IL-4-induced DNA-binding protein factor in murine B cells designated NF-IL-4-gamma 1. This factor binds specifically to a site within a 13-bp DNA sequence extending from -125 to -113 (5' CATTCACATGAAG 3') in the germ-line gamma 1 promoter and shown previously to be important for IL-4-responsive transcription. This sequence is highly homologous to the IFN-gamma activation site or GAS, and competitive binding studies demonstrate that NF-IL-4-gamma 1 can also bind to GAS elements in the promoters of two IFN-gamma-responsive genes and to an IL-4-responsive element in the germ-line epsilon Ig promoter. NF-IL-4-gamma 1 is rapidly induced in the absence of de novo protein synthesis and expression is sustained through day 4 of in vitro culture with IL-4 and LPS. Induction of NF-IL-4-gamma 1 is inhibited by the kinase inhibitor staurosporine and the factor itself requires phosphorylation for binding activity. The binding specificity and expression characteristics of NF-IL-4-gamma 1 suggest identity with other recently described IL-4-activated, GAS-binding factors that are members of the signal transducers and activators of transcription (STAT) family of cytokine-responsive transcription factors.