Constitutively active NF-κB triggers systemic TNFα-dependent inflammation and localized TNFα-independent inflammatory disease

Jie Dong, Eijiro Jimi, Caroline Zeiss, Matthew S. Hayden, Sankar Ghosh

研究成果: Contribution to journalArticle査読

68 被引用数 (Scopus)

抄録

NF-κB is well established as a key component of the inflammatory response. However, the precise mechanisms through which NF-κB activation contributes to inflammatory disease states remain poorly defined. To test the role of NF-κB in inflammation, we created a knock-in mouse that expresses a constitutively active form of NF-κB p65 dimers. These mice are born at normal Mendelian ratios, but display a progressive, systemic hyper-inflammatory condition that results in severe runting and, typically, death 8-20 d after birth. Examination of homozygous knock-in mice demonstrates significant increases in proinflammatory cytokines and chemokines. Remarkably, crossing this strain with mice lacking TNF receptor 1 (TNFR1) leads to a complete rescue of the hyperinflammatory phenotype. However, upon aging, these rescued mice begin to display chronic keratitis accompanied by increased corneal expression of TNFα, IL-1β, and MMP-9, similar to that seen in human keratoconjunctivitis sicca (KCS) or "dry eyes." Therefore, our results show that, while constitutively active NF-κB can trigger systemic inflammation, it does so indirectly, through increased TNF production. However, certain inflammatory disease states, such as keratitis or KCS, a condition that is seen in Sjogren's syndrome, are dependent on NF-κB, but are independent of TNFR1 signaling.

本文言語英語
ページ(範囲)1709-1717
ページ数9
ジャーナルGenes and Development
24
16
DOI
出版ステータス出版済み - 8 15 2010
外部発表はい

All Science Journal Classification (ASJC) codes

  • 遺伝学
  • 発生生物学

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