NF-κB activates IL-6 expression through cooperation with c-Jun and IL6-AP1 site, but is independent of its IL6-NFκB regulatory site in autocrine human multiple myeloma cells

Abstract

IL-6 stimulates the growth and survival of a variety of tumors. In multiple myeloma (MM), IL-6 prevents spontaneous, drug-induced, and Fas-induced apoptosis. The sources of IL-6 in multiple myeloma appear to be both autocrine and paracrine in nature, with autocrine MM cells exhibiting a constitutively activated expression of the cytokine. Here we present a systematic analysis of the functional roles of the four major transcriptional regulatory sites present in the IL-6 promoter region, IL6-NFκB, IL6-C/EBP, IL6-CREB and IL6-AP1. Among these regulatory sites, IL6-AP1 is the most important cis-regulatory site, and plays a vital role in the constitutive expression of IL-6 in IM9 cells. Conversely, the IL6-CREB site, when bound by the transcription factor CREB, exhibits a repression of IL-6 autocrine expression, a result of possible steric hinderence of C/EBP-β, due to the close proximity and site overlap between the IL6-C/EBP and IL6-CREB sites. Uniquely, although the presence of NF-κB protein is fundamental for constitutive expression of IL-6, a functional NF-κB site on the IL-6 promoter region is not required. The mechanism of NF-κB activation of IL-6 appears to occur through the cooperation with c-Jun protein, that constitutively occupies the IL6-AP1 site, and this indicates a novel transcriptional mechanism for NF-κB in the activation of NF-κB-driven genes. ©2004 Landes Bioscience.