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 H2O 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. H2O2-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. Copyright

Original languageEnglish
Pages (from-to)863-873
Number of pages11
JournalEuropean Respiratory Journal
Volume40
Issue number4
DOIs
Publication statusPublished - Oct 1 2012

Fingerprint

Chronic Obstructive Pulmonary Disease
Interleukin-8
Inflammation
Blood Cells
Oxidative Stress
3'-(1-butylphosphoryl)adenosine
RNA Polymerase II
DNA-Binding Proteins
Mortality

Keywords

  • Interleukin-8/CXCL8
  • Oxidative stress
  • Peripheral blood mononuclear cell
  • RNA polymerase II

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Reduced nuclear factor-κB repressing factor : A link toward systemic inflammation in COPD. / Lee, Kang Yun; Ho, Shu Chuan; Chan, Yao Fei; Wang, Chun Hua; Huang, Chien Da; Liu, Wen Te; Lin, Shu Min; Lo, Yu Lun; Chang, Ya Ling; Kuo, Lu Wei; Kuo, Han Pin.

In: European Respiratory Journal, Vol. 40, No. 4, 01.10.2012, p. 863-873.

Research output: Contribution to journalArticle

Lee, Kang Yun ; Ho, Shu Chuan ; Chan, Yao Fei ; Wang, Chun Hua ; Huang, Chien Da ; Liu, Wen Te ; Lin, Shu Min ; Lo, Yu Lun ; Chang, Ya Ling ; Kuo, Lu Wei ; Kuo, Han Pin. / Reduced nuclear factor-κB repressing factor : A link toward systemic inflammation in COPD. In: European Respiratory Journal. 2012 ; Vol. 40, No. 4. pp. 863-873.
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AU - Lee, Kang Yun

AU - Ho, Shu Chuan

AU - Chan, Yao Fei

AU - Wang, Chun Hua

AU - Huang, Chien Da

AU - Liu, Wen Te

AU - Lin, Shu Min

AU - Lo, Yu Lun

AU - Chang, Ya Ling

AU - Kuo, Lu Wei

AU - Kuo, Han Pin

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N2 - 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 H2O 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. H2O2-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. Copyright

AB - 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 H2O 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. H2O2-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. Copyright

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KW - Oxidative stress

KW - Peripheral blood mononuclear cell

KW - RNA polymerase II

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