Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8.

TLDR

NF‑IL6 and NF‑κB binding sites in the IL‑6 promoter are essential for transcriptional regulation, and similar sites in many inflammatory genes suggest a broader cooperative role. The study investigates the synergistic activation of IL‑6 and IL‑8 promoters by NF‑IL6 and NF‑κB and explores how viral proteins might modulate this interaction. Co‑transfection of NF‑IL6 and NF‑κB p65 produced strong synergistic activation of IL‑6 and IL‑8 promoter reporters, requiring both binding sites and involving direct interaction between NF‑IL6’s basic leucine‑zipper domain and p65’s Rel homology domain.

Abstract

Single binding sites for transcription factors NF-IL6 and NF-kappa B are present in the promoter of the interleukin (IL) 6 gene. Previous studies of internally deleted promoter mutants demonstrated that these two sites are important for the transcriptional regulation of this gene. In this report, we describe the synergistic activation of the IL-6 promoter by transcription factors NF-IL6 and NF-kappa B. Cotransfection of NF-IL6 with the NF-kappa B p65 subunit resulted in strong synergistic activation of an IL-6 promoter-reporter construct. Both the NF-IL6 and NF-kappa B binding sites in the IL-6 promoter were required for synergistic activation. Similar synergistic activation was observed in the IL-8 promoter, which also contains both NF-IL6 and NF-kappa B binding sites. Furthermore, we demonstrated that NF-IL6 and the NF-kappa B p65 subunit directly associated via the basic leucine-zipper domain of NF-IL6 and the Rel homology domain of p65. Since the promoters of many other genes involved in the inflammatory and acute-phase responses also contain binding sites for NF-IL6 and NF-kappa B, the cooperation between these two factors may have an important role in these responses. We also discuss the possible interplay between various viral gene products and these two factors in the process of viral infection and constitutive cytokine production.