INVOLVEMENT OF A NF-KAPPA-B-LIKE TRANSCRIPTION FACTOR IN THE ACTIVATION OF THE INTERLEUKIN-6 GENE BY INFLAMMATORY LYMPHOKINES

Interleukin-6 (IL-6) is one of the major mediators of inflammation, and its expression is inducible by the other inflammatory lymphokines, interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α). We demonstrate that a common IL-6 promoter element, termed inflammatory lymphokine-responsive element (ILRE), is important for induction of IL-6 gene expression by IL-1 and TNF-α despite possible differences in the mechanisms of action of these lymphokines. Remarkably, the ILRE sequence, located between -73 to -63 relative to the mRNA cap site, is highly homologous to NF-κB transcription factor-binding motifs and binds an IL-1-TNF-α-inducible nuclear factor; the sequence specificities, binding characteristics, and subcellular localizations of this factor are indistinguishable from those of NF-κB. In addition, mutations of the ILRE sequence which impair the binding of this nuclear factor abolished the induction of IL-6 gene expression by IL-1 and TNF-α in vivo. These results indicate that a nuclear factor indistinguishable from NF-κB is involved in the transcriptional activation of the IL-6 gene by IL-1 and TNF-α.