A NOVEL ENHANCER ELEMENT IN THE HUMAN IL-4 PROMOTER IS SUPPRESSED BY A POSITION-INDEPENDENT SILENCER

IL-4 is a pleiotropic cytokine that regulates T cell-dependent immune responses. We identified and characterized a novel enhancer, positive regulatory element I (PRE-I), in the 5' region of the promoter of the human IL-4 gene. The functional core element of PRE-I is -239GTGTAATTT CCTATGC-224. Two novel nuclear proteins, POS-1 and POS-2, were found t o specifically bind to the core element and function as transcriptiona l activators. The function of PRE-I did not require T cell stimulation and was not restricted to T cells. However, mutations in the core ele ment of PRE-I significantly reduced the promoter activity and complete ly impaired inducibility of the promoter. In the human IL-4 promoter t he enhancer function of PRE-I is strongly suppressed. A negative regul atory element (NRE), 45 bp upstream of PRE-I, directly represses PRE-I enhancer activity. Repression of PRE-I by NRE does not require a part icular order or arrangement of positive and negative regulatory-sequen ces. The IL-4 NRE may also down-regulate other enhancers, such as the murine sarcoma virus and the SV40 enhancers. Thus, the IL-4 NRE may re present a new type of cis regulatory element that carries the properti es of a silencer but down-regulates enhancer instead of basal promoter activity.