IL-6 signals activate an IL-6 response element in the junB promoter, JRE-IL6, in a Ras-independent manner. IL-6 rapidly induced a DNA-binding activity to the Ets binding site of JRE-IL6 (JEBS), one of necessary DNA motifs of the IL-6 response element. The IL-6-induced JEBS-binding activity was indistinguishable from those to acute phase response element (APRE) in both kinetics of induction and its DNA-binding specificity. Purified APRE binding factors (APRFs) from IL-6-stimulated rat liver were found to be composed of multiple Stat3-related proteins and Stat1. Moreover the purified APRFs specifically made a complex with JRE-IL6 with the same mobility as that observed in the crude extracts. These results indicate that an immediate early signal of IL-6 leading to activation of JRE-IL6 is mediated by STAT family transcription factors.