Heme oxygenase 1 attenuates the development of atopic dermatitis-like lesions in mice: implications for human disease.
BACKGROUND
Oxidative stress has been implicated in the exacerbation of atopic dermatitis (AD).


OBJECTIVE
We sought to investigate the pathophysiologic roles of inducible antioxidant heme oxygenase (HO) 1 in the development of AD.


METHODS
Serum HO-1 levels of patients with AD (n = 100) and age-matched healthy control subjects (n = 72) were determined by means of ELISA. The relationships between serum HO-1 levels and clinical severities, laboratory parameters, and cytokines/chemokines were assessed. Skin lesions of patients with AD and psoriasis were analyzed by means of immunohistochemistry. A murine AD model, DS-Nh, was used to further investigate localization and function of HO-1. Evaluation of symptoms, serum IgE and IL-18 levels, immunoblotting results, and histologic analyses of skin were performed. The effect of intraperitoneally administered hemin, a potent HO-1 inducer, or zinc protoporphyrin IX, an inhibitor of HO, was monitored.


RESULTS
Serum HO-1 levels were significantly increased in patients with AD compared with those seen in healthy control subjects and were associated with AD disease severity. Serum HO-1 levels correlated with serum IgE, lactate dehydrogenase, IL-18, and thymus and activation-regulated chemokine levels. HO-1-expressing cells were accumulated in skin lesions of patients with AD and DS-Nh mice. Immunofluorescence of mouse skin lesions revealed that HO-1-positive cells were macrophages and dendritic cells. Treatment with hemin, but not with zinc protoporphyrin IX, attenuated the development of the skin lesions in DS-Nh mice and reduced serum IL-18 levels.


CONCLUSIONS
HO-1 levels were increased in sera and skin lesions of patients with AD. Enhancement of HO-1 attenuated the development of skin lesions in mice, suggesting that HO-1 induction offers a promising therapeutic strategy for AD.
Kirino
Mio
M
Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Kirino
Yohei
Y
Takeno
Mitsuhiro
M
Nagashima
Yoji
Y
Takahashi
Kazuo
K
Kobayashi
Masayoshi
M
Murakami
Shuji
S
Hirasawa
Tsutomu
T
Ueda
Atsuhisa
A
Aihara
Michiko
M
Ikezawa
Zenro
Z
Ishigatsubo
Yoshiaki
Y
D000328:Adult; D000818:Animals; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D006427:Hemin / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D020382:Interleukin-18 / Q000097:blood; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D011524:Protoporphyrins / Q000008:administration & dosage / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology
D020382:Interleukin-18; D011524:Protoporphyrins; C017803:zinc protoporphyrin; D006427:Hemin; D051547:Heme Oxygenase-1