Targeted disruption of NF-κB1 (p50) augments cigarette smoke-induced lung inflammation and emphysema in mice: a critical role of p50 in chromatin remodeling

Saravanan Rajendrasozhan, Sangwoon Chung, Isaac K Sundar, Hongwei Yao, Irfan Rahman

Research output: Contribution to journalArticlepeer-review

Abstract

NF-kappaB-mediated proinflammatory response to cigarette smoke (CS) plays a pivotal role in the pathogenesis of chronic obstructive pulmonary disease (COPD). The heterodimer of RelA/p65-p50 (subunits of NF-kappaB) is involved in transactivation of NF-kappaB-dependent genes, but interestingly p50 has no transactivation domain. The endogenous role of p50 subunit, particularly in regulation of CS-mediated inflammation in vivo, is not known. We therefore hypothesized that p50 subunit plays a regulatory role on RelA/p65, and genetic ablation of p50 (p50(-/-)) leads to increased lung inflammation and lung destruction in response to CS exposure in mouse. To test this hypothesis, p50-knockout and wild-type (WT) mice were exposed to CS for 3 days to 6 mo, and inflammatory responses as well as air space enlargement were assessed. Lungs of p50-deficient mice showed augmented proinflammatory response to acute and chronic CS exposures as evidenced by increased inflammatory cell influx and proinflammatory mediators release such as monocyte chemoattractant protein-1 (MCP-1) and interferon-inducible protein-10 (IP-10) compared with WT mice. IKK2 inhibitor (IMD-0354), which reduces the nuclear translocation of RelA/p65, attenuated CS-mediated neutrophil influx in bronchoalveolar lavage fluid and cytokine (MCP-1 and IP-10) levels in lungs of WT but not in p50-deficient mice. Importantly, p50 deficiency resulted in increased phosphorylation (Ser276 and Ser536), acetylation (Lys310), and DNA binding activity of RelA/p65 in mouse lung, associated with increased chromatin remodeling evidenced by specific phosphoacetylation of histone H3 (Ser10/Lys9) and acetylation of H4 (Lys12) in response to CS exposure. Surprisingly, p50-null mice showed spontaneous air space enlargement, which was further increased after CS exposure compared with WT mice. Thus our data showed that p50 endogenously regulates the activity of RelA/p65 by decreasing its phosphoacetylation and DNA binding activity and specific histone modifications and that genetic ablation of p50 leads to air space enlargement in mouse.
Original languageEnglish
Pages (from-to)L197-209
Number of pages13
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume298
Issue number2
DOIs
Publication statusPublished - Feb 2010

Keywords

  • Animals
  • Chromatin Assembly and Disassembly
  • Gene Targeting
  • Humans
  • I-kappa B Kinase
  • I-kappa B Proteins
  • Lung
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B p50 Subunit
  • Neutrophils
  • Pneumonia
  • Pulmonary Emphysema
  • Smoke
  • Smoking
  • Transcription Factor RelA

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