NF-kappaB activates IL-6 expression through cooperation with c-Jun and IL6-AP1 site, but is independent of its IL6-NFkappaB regulatory site in autocrine human multiple myeloma cells.
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-NFkappaB, 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-beta, due to the close proximity and site overlap between the IL6-C/EBP and IL6-CREB sites. Uniquely, although the presence of NF-kappaB protein is fundamental for constitutive expression of IL-6, a functional NF-kappaB site on the IL-6 promoter region is not required. The mechanism of NF-kappaB 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-kappaB in the activation of NF-kappaB-driven genes.
Xiao
Weihua
W
Basic Research Program, SAIC Frederick, Frederick, Maryland, USA.
Hodge
David R
DR
Wang
Lihua
L
Yang
Xiaoyi
X
Zhang
Xiaohu
X
Farrar
William L
WL
D022782:CCAAT-Enhancer-Binding Protein-beta / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D012045:Regulatory Sequences, Nucleic Acid; D017384:Sequence Deletion; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D022782:CCAAT-Enhancer-Binding Protein-beta; D017362:Cyclic AMP Response Element-Binding Protein; D015850:Interleukin-6; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1