NFκB and AP-1 Drive Human Myometrial IL8 Expression

Abstract

The uterine expression of the chemokine IL8 increases dramatically with the onset of labour both at term and preterm. The IL8 promoter contains binding sites for the transcription factors nuclear factor-kappa B (NFκB), activator protein-1 (AP-1), and CCAAT/enhancer-binding protein (CEBP). In this study we investigated the roles of these transcription factors in IL1B regulation of the IL8 gene in human myometrium. Using chromatin immune precipitation (ChIP) assay, we showed that each of NFκB, CEBP, and AP-1 binds to the IL8 promoter upon IL1B stimulation. To examine the relative importance of each site in IL8 gene expression, site-directed mutagenesis of each of these sites was performed. We found that the NFκB site was essential for basal and IL1B-stimulated gene expression. Mutation of the AP-1 site reduced both basal and IL1B-stimulated expression but to a lesser extent. Mutation of the CEBP site had no effect upon basal expression but eliminated the IL1B response. Small interfering RNA (siRNA) silencing of NFκB abolished the IL8 response to IL1B significantly; siRNA against AP-1 reduced it to a lesser extent whilst knockdown of CEBP enhanced the response. Our data confirms a central and essential role for NFκB in regulation of IL8 in human myometrium.

MicroRNA miR-93-5p regulates expression of IL-8 and VEGF in neuroblastoma SK-N-AS cells

“…Another protein firmly involved in angiogenesis of neuroblastoma is vascular endothelial growth factor (VEGF) (5,6). As expected, one of the control levels is transcription-related to the interaction between IL-8 and VEGF promoters and different transcription factors, such as NF-κB, AP-1 and C-EBP/NF-IL-6 (7)(8)(9)(10)(11)(12). In addition, the expression of IL-8 and VEGF genes may be under the control of epigenetic mechanisms, such as those regulated by microRNAs in cancer, differentiation and inflammatory processes (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”

Early growth response protein-1 mediates lipotoxicity-associated placental inflammation: role in maternal obesity

“…Moreover, the observed association between increased JNK signaling and EGR-1 protein in obese placenta may suggest that EGR-1 can mediate obesity-induced placental inflammation and warrants further investigation. DNA binding sites for NF-B, AP-1, and EGR-1 have been described in the promoters of a number of inflammatory cytokine genes including TNF␣ (73), IL-6 (13,26,35) and IL-8 (26,33), indicating direct regulation of cytokine expression by these transcription factors. Importantly, studies have shown that combinations of transcription factor binding are required for transactivation of proinflammatory cytokine expression in an inducer-specific manner (11,13,21,29,73,77).…”

Oxidative stress-inducible truncated serine/arginine-rich splicing factor 3 regulates interleukin-8 production in human colon cancer cells

“…The human IL-8 gene promoter contains a number of regulatory cis elements that are activated by the interaction with AP-1, CCAAT/enhancer-binding protein (C/EBP), and nuclear factor-B (NF-B) (15). The transcription start site of the IL-8 gene is located 101 bp upstream of the translation site.…”