title: NF-κB inducing kinase, NIK mediates cigarette smoke/TNFα-induced histone acetylation and inflammation through differential activation of IKKs.
abstract: BACKGROUND
  Nuclear 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.
  
  
  METHODS
  To 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.
  
  
  CONCLUSIONS
  Overall, our findings provide a novel role for NIK in CS- and TNFα-induced histone acetylation, especially on histone H3K9.
authors: Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York, United States of America.
authors: Sangwoon
authors: S
authors: Chung
authors: Isaac K
authors: IK
authors: Sundar
authors: Jae-Woong
authors: JW
authors: Hwang
authors: Fiona E
authors: FE
authors: Yull
authors: Timothy S
authors: TS
authors: Blackwell
authors: Vuokko L
authors: VL
authors: Kinnula
authors: Michael
authors: M
authors: Bulger
authors: Hongwei
authors: H
authors: Yao
authors: Irfan
authors: I
authors: Rahman
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation / Q000150:complications / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D012907:Smoking / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D006657:Histones; D051550:I-kappa B Kinase; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase