Abstract
BackgroundNuclear factor (NF)-κB inducing kinase (NIK) is a central player in the non-canonical NF κB pathway, which phosphorylates IκB kinase α (IKKα) resulting in enhancement of target gene expression. We have recently shown that IKKα responds to a variety of stimuli including oxidants and cigarette smoke (CS) regulating the histone modification in addition to its role in NF-κB activation. However, the primary signaling mechanism linking CS-mediated oxidative stress and TNFα with histone acetylation and pro-inflammatory gene transcription is not well understood. We hypothesized that CS and TNFα increase NIK levels causing phosphorylation of IKKα, which leads to histone acetylation.MethodologyTo test this hypothesis, we investigated whether NIK mediates effects of CS and TNFα on histone acetylation in human lung epithelial cells in vitro and in lungs of mouse exposed to CS in vivo. CS increased the phosphorylation levels of IKKα/NIK in lung epithelial cells and mouse lungs. NIK is accumulated in the nuclear compartment, and is recruited to the promoters of pro-inflammatory genes, to induce posttranslational acetylation of histones in response to CS and TNFα. Cells in which NIK is knocked down using siRNA showed partial attenuation of CSE- and TNFα-induced acetylation of histone H3 on pro-inflammatory gene promoters. Additional study to determine the role of IKKβ/NF-κB pathway in CS-induced histone acetylation suggests that the canonical pathway does not play a role in histone acetylation particularly in response to CS in mouse lungs.ConclusionsOverall, our findings provide a novel role for NIK in CS- and TNFα-induced histone acetylation, especially on histone H3K9.
Highlights
Cigarette smoke (CS) contains numerous reactive oxygen/ nitrogen species, reactive aldehydes, and quinones [1], which are involved in the pathogenesis of chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD) and lung cancer [2,3,4,5]
Overall, our findings provide a novel role for NFkB inducing kinase (NIK) in cigarette smoke (CS)- and Tumor necrosis factor a (TNFa)-induced histone acetylation, especially on histone H3K9
CS and TNFa activate NIK-IkB kinase a (IKKa) non-canonical pathway We determined whether the abundance of NIK was increased by cigarette smoke extract (CSE) and TNFa in H292 and normal human bronchial/tracheal epithelial (NHBE) cells
Summary
Cigarette smoke (CS) contains numerous reactive oxygen/ nitrogen species, reactive aldehydes, and quinones [1], which are involved in the pathogenesis of chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD) and lung cancer [2,3,4,5]. Studies from our laboratory have shown that CS induced the inflammatory response in macrophages [9,10] and airway epithelial cells [11,12]. Both of these cell types can influence airway inflammation leading to airway abnormalities in COPD. Inhalation of CS and airborne particulate matter resulted in lung injury by generation of oxidative stress, leading to cascades of signaling events triggering the production of cytokines, chemokines, and other factors [7,13,14]. The primary signaling mechanism linking CS-mediated oxidative stress and TNFa with histone acetylation and pro-inflammatory gene transcription is not well understood. We hypothesized that CS and TNFa increase NIK levels causing phosphorylation of IKKa, which leads to histone acetylation
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