Overexpression of HO-1 protects against TNF-α-mediated airway inflammation by down-regulation of TNFR1-dependent oxidative stress

I-Ta Lee, Shue Fen Luo, Chiang Wen Lee, Shyi Wu Wang, Chih Chung Lin, Chia Chi Chang, Yuh Lien Chen, Lee Young Chau, Chuen Mao Yang

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Abstract

Oxidative stresses are believed to play an important role in the induction of both cell adhesion molecules and pro-inflammatory cytokines, a key event in a variety of inflammatory processes. The enzyme heme oxygenase-1 (HO-1) functions as an antioxidant and serves to protect against tissue injury. In this study, we report that HO-1 was induced in cultured human tracheal smooth muscle cells after either treatment with a potent inducer of HO-1 activity, cobalt protoporphyrin IX, or infection with a recombinant adenovirus that carries the human HO-1 gene. Overexpression of HO-1 protected against tumor necrosis factor (TNF)-α-mediated airway inflammation via the down-regulation of oxidative stress, adhesion molecules, and interleukin-6 in both cultured human tracheal smooth muscle cells and the airways of mice. In addition, HO-1 overexpression inhibited TNF-α-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, adherence of THP-1 cells, generation of interleukin-6, p47phox translocation, and nuclear factor-κB activation. HO-1 overexpression also attenuated TNF-α-induced oxidative stress, which was abrogated in the presence of both the HO-1 inhibitor, zinc protoporphyrin IX, as well as a carbon monoxide scavenger. In addition, HO-1 overexpression reduced the formation of a TNFR1/c-Src/p47phox complex. These results suggest that HO-1 functions as a suppressor of TNF-α signaling, not only by inhibiting the expression of adhesion molecules and generation of interleukin-6, but also by diminishing intracellular reactive oxygen species production and nuclear factor-κB activation in both cultured human tracheal smooth muscle cells and the airways of mice.

Original languageEnglish
Pages (from-to)519-532
Number of pages14
JournalAmerican Journal of Pathology
Volume175
Issue number2
DOIs
Publication statusPublished - Jan 1 2009
Externally publishedYes

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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