JAK-STAT PATHWAY IS INVOLVED IN THE INDUCTION OF TNF-BETA GENE DURINGSTIMULATION BY IL-2

IL-2 is the major regulatory cytokine of the immune system. It plays a key role in T cell survival, growth and activation. IL-2 may induce t he expression of multiple genes including some cytokine genes. The ind uction of these genes is triggered by different signal pathways, one o f them being the Jak-STAT signal pathway. The genes regulated by this pathway remain to be determined. By studying IL-2-inducible genes, we have confirmed that the TNF-beta gene is one of the immediate early ge nes activated by IL-2. By analysis of the DNA sequences around 180-300 bases upstream of the transcription initiation point of the mouse TNF -beta gene, we demonstrate that there is a STAT5 binding site which is essential to the inducibility of the TNF-beta gene. Furthermore, in B A/F3 cells co-transfected with the STAT5A gene and IL-2R beta gene, th e activation of the TNF-B gene promoter by IL-2 was greatly promoted, whereas the TNF-beta gene promoter became IL-2-non-inducible if the ST AT5A gene was substituted with a dominant negative STAT5A, i.e. a C-te rminally truncated mutant. Taken together, our results show that the J ak-STAT signal pathway is involved in induction of the TNF-beta gene i n cells stimulated by IL-2.