NF-κB Inducing Kinase, NIK Mediates Cigarette Smoke/TNFα-Induced Histone Acetylation and Inflammation through Differential Activation of IKKs

Background: Nuclear factor (NF)-kappa B inducing kinase (NIK) is a central player in the non-canonical NF kappa B pathway, which phosphorylates I kappa B kinase alpha (IKK alpha) resulting in enhancement of target gene expression. We have recently shown that IKK alpha responds to a variety of stimuli including oxidants and cigarette smoke (CS) regulating the histone modification in addition to its role in NF-kappa B activation. However, the primary signaling mechanism linking CS-mediated oxidative stress and TNF alpha with histone acetylation and pro-inflammatory gene transcription is not well understood. We hypothesized that CS and TNF alpha increase NIK levels causing phosphorylation of IKKa, which leads to histone acetylation. Methodology: To test this hypothesis, we investigated whether NIK mediates effects of CS and TNF alpha 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 IKK alpha/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 TNF alpha. Cells in which NIK is knocked down using siRNA showed partial attenuation of CSE- and TNF alpha-induced acetylation of histone H3 on pro-inflammatory gene promoters. Additional study to determine the role of IKK beta/NF-kappa B 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. Conclusions: Overall, our findings provide a novel role for NIK in CS- and TNF alpha-induced histone acetylation, especially on histone H3K9.