title: Reduced nuclear factor-κB repressing factor: a link toward systemic inflammation in COPD.
abstract: Chronic systemic inflammation is implicated in the systemic manifestations and, probably, the excess mortality risk of chronic obstructive pulmonary disease (COPD). The role of nuclear factor (NF)-κB repressing factor (NRF), a DNA-binding, protein-inhibiting NF-κB response gene, in human diseases has not been explored. We hypothesised that the NRF-negative regulatory mechanism is impaired in COPD peripheral blood mononuclear cells (PBMCs) leading to excessive interleukin (IL)-8/CXCL8 production. NRF expression, NF-κB activation, IL-8/CXCL8 release and intracellular oxidative stress were assessed in PBMCs of normal subjects and stable COPD patients. Primary PBMCs with NRF overexpression, NRF knockdown and exposure to H(2)O(2) were used to elucidate the mechanisms. Stable COPD patients, especially those with severe COPD, showed decreased NRF expression, enhanced NF-κB activation and increased IL-8/CXCL8 release in PBMCs compared with normal subjects. This was associated with reduced NRF and increased RNA polymerase II occupancy at the IL-8/CXCL8 promoter. NRF knockdown enhanced IL-8/CXCL8 production in normal PBMCs, whilst NRF overexpression attenuated IL-8/CXCL8 production. Intracellular oxidative stress was increased in COPD PBMCs. H(2)O(2)-decreased NRF expression and -enhanced IL-8/CXCL8 production was augmented in COPD PBMCs. NRF expression is reduced in PBMCs of stable COPD patients, probably through oxidative stress, leading to increased production of IL-8/CXCL8 and potentially chronic systemic inflammation.
authors.affiliation: Dept of Thoracic Medicine Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 199 Tun-Hwa North Road, Taipei, Taiwan.
authors.forename: Kang-Yun
authors.initials: KY
authors.lastname: Lee
authors.forename: Shu-Chuan
authors.initials: SC
authors.lastname: Ho
authors.forename: Yao-Fei
authors.initials: YF
authors.lastname: Chan
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Wang
authors.forename: Chien-Da
authors.initials: CD
authors.lastname: Huang
authors.forename: Wen-Te
authors.initials: WT
authors.lastname: Liu
authors.forename: Shu-Min
authors.initials: SM
authors.lastname: Lin
authors.forename: Yu-Lun
authors.initials: YL
authors.lastname: Lo
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Chang
authors.forename: Lu-Wei
authors.initials: LW
authors.lastname: Kuo
authors.forename: Han-Pin
authors.initials: HP
authors.lastname: Kuo
mesh_terms: D000368:Aged; D015153:Blotting, Western; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D012319:RNA Polymerase II; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D016209:Interleukin-8; D016328:NF-kappa B; C111027:NKRF protein, human; D012097:Repressor Proteins; D012319:RNA Polymerase II