In seeking a common intracellular mediator of gene activation by IL 1, we have identified the transcription factor AP-1. The AP-1 factor consists of c-Jun and c-fos proteins. IL 1 first activates a novel set of transcription factors that induce transcription of the c-jun promoter. The mRNA for c-jun is then stabilized, leading to a large accumulation of this message. IL 1 also induces c-fos transcription in some cells. The resulting increased production of c-Jun and c-fos proteins yield high amounts of the AP-1 transcription factor, which can subsequently induce many genes. A second project addresses the extremely broad range of activities that have been attributed to IL 1. Of these many effects, which ones are actually important in vivo? To address this question we are creating IL 1-less mice by gene targeting. We have produced targeting constructs for IL 1beta and introduced them into an embryonic stem cell line. We have identified cell clones with targeted IL 1beta genes, and they will be used to produce mice lacking the targeted gene; these mice will be extensively studied for physiological abnormalities. A third project concerns the wide range of binding specificities of the immune system that is generated by gene rearrangement. During early T- cell development coding sequences for variable and joining regions are recombined, thus creating a new unique T-cell receptor gene. We have successfully developed the first in vitro system to study signals for rearrangement of the TCRbeta chain. We found that interleukin 7 can induce TCRbeta chain rearrangement in unrearranged T-cell precursors. Using radiation chimeras we have generated a synchronized T-cell population that is undergoing rearrangement. Nuclear proteins of these cells served as a source to study components of the recombination machinery. We identified a protein complex that specifically binds to the recombination sequence which presumably serves as a target for the rearrangement machinery.
