NF-kappa B/p50 and NF-kappa B/c-Rel differentially regulate the activity of the 3 'alpha E-hsl,2 enhancer in normal murine B cells in an activation-dependent manner

The enhancer complex located 3' to the C(H)alpha gene in the IgH locus (3 a lpha E) may regulate a cell function through its ability to act as a locus control region. Multiple, functionally relevant NF-kappa B binding sites ar e located within the 3'alpha E, NF-kappa B subunits, especially p50 and c-R el, have also been shown to play critical and differential roles in regulat ing a cell proliferation, Ig secretion, germline CH transcription and Ig cl ass switching. Thus, NF-kappa B could regulate a cell function in part thro ugh modulation of 3'alpha E activity. In this study we determined whether p 50 and/or c-Rel regulate 3'alpha E activity in normal murine a cells and wh ether this depends on the nature of the a cell activator. For this purpose, we crossed p50- and c-Rel-deficient mice with mice that are transgenic for a 3'alpha E-hsl,2-human beta-globin reporter gene, and established p50(-/- ) or c-Rel(-/-) mice homozygous for the enhancer transgene. We show, using optimal stimulating conditions, that p50 selectively augments 3'alpha E-hs1 ,2 activity in lipopolysaccharide-activated a cells, whereas c-Rel is requi red for optimal 3'alpha E-hs1,2 induction in a cells activated through CD40 .