IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells

Abstract

Inflammatory stimuli triggers the degradation of three inhibitory κB (IκB) proteins, allowing for nuclear translocation of nuclear factor-κB (NFκB) for transcriptional induction of its target genes. Of these three, IκBα is a well-known negative feedback regulator that limits the duration of NFκB activity. We sought to determine whether IκBα’s role in enabling or limiting NFκB activation is important for tumor necrosis factor (TNF)-induced gene expression in human breast cancer cells (MCF-7). Contrary to our expectations, many more TNF-response genes showed reduced induction than enhanced induction in IκBα knockdown cells. Mathematical modeling was used to investigate the underlying mechanism. We found that the reduced activation of some NFκB target genes in IκBα-deficient cells could be explained by the incoherent feedforward loop (IFFL) model. In addition, for a subset of genes, prolonged NFκB activity due to loss of negative feedback control did not prolong their transient activation; this implied a multi-state transcription cycle control of gene induction. Genes encoding key inflammation-related transcription factors, such as JUNB and KLF10, were found to be best represented by a model that contained both the IFFL and the transcription cycle motif. Our analysis sheds light on the regulatory strategies that safeguard inflammatory gene expression from overproduction and repositions the function of IκBα not only as a negative feedback regulator of NFκB but also as an enabler of NFκB-regulated stimulus-responsive inflammatory gene expression. This study indicates the complex involvement of IκBα in the inflammatory response to TNF that is induced by radiation therapy in breast cancer.

Comparing the Blood Response to Hyperbaric Oxygen with High-Intensity Interval Training—A Crossover Study in Healthy Volunteers

“…NFKBIA codes for one of three inhibitory κB (IκB) proteins regulating NFκB. IκBα has a complex dynamic role in regulation of TNF-induced NFκB target genes [43]. AIP3 codes for tumor necrosis factor alpha-induced protein 3, also known as A20, is a key regulator of inflammatory signaling to preserve tissue immune homeostasis, and is involved in a plethora of chronic inflammatory and auto-immune diseases [44].…”

Histopathology of Pre-diabetic White Rat (Rattus norvegicus L.) Renal After Treatment with Turmeric Powder and Organic Quail Eggs

“…Inhibiting NF-KB and IκBA suppresses proximal tubular cell inflammation. IκBA functions as a negative feedback regulator, limiting NF-KB activity (Ando et al, 2021).…”

Tonic TNF conditioning of macrophages safeguards stimulus‐specific inflammatory responses

“…The stimulus information contained in NFκB dynamics is decoded in the nucleus. Target genes are capable of distinguishing among peak activation fold (Lee et al , 2014), duration (Hoffmann et al , 2002; Sen et al , 2020), and speed (Ando et al , 2021). Interestingly, oscillatory dynamics (elicited by TNF) safeguard the epigenome, whereas non‐oscillatory dynamics (elicited by PAMPs) lead to epigenomic reprogramming (Cheng et al , 2021).…”