Overexpression of HO-1 protects against TNF-alpha-mediated airway inflammation by down-regulation of TNFR1-dependent oxidative stress.
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)-alpha-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-alpha-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, adherence of THP-1 cells, generation of interleukin-6, p47(phox) translocation, and nuclear factor-kappaB activation. HO-1 overexpression also attenuated TNF-alpha-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/p47(phox) complex. These results suggest that HO-1 functions as a suppressor of TNF-alpha 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-kappaB activation in both cultured human tracheal smooth muscle cells and the airways of mice.
Lee
I-Ta
IT
Department of Pharmacology, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan, Taiwan.
Luo
Shue-Fen
SF
Lee
Chiang-Wen
CW
Wang
Shyi-Wu
SW
Lin
Chih-Chung
CC
Chang
Chia-Chi
CC
Chen
Yuh-Lien
YL
Chau
Lee-Young
LY
Yang
Chuen-Mao
CM
D000818:Animals; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002460:Cell Line; D015536:Down-Regulation; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006801:Humans; D051379:Mice; D009130:Muscle, Smooth / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D011524:Protoporphyrins / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D014136:Tracheitis / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism
D015815:Cell Adhesion Molecules; D016328:NF-kappa B; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D019061:src-Family Kinases