IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions
- Hiroshi Konishi*,†,
- Hiroko Tsutsui†,‡,
- Takaaki Murakami*,†,
- Shizue Yumikura-Futatsugi†,‡,
- Kei-ichi Yamanaka*,†,
- Minoru Tanaka§,
- Yohichiro Iwakura¶,
- Noboru Suzuki∥,
- Kiyoshi Takeda†,**,
- Shizuo Akira†,**,
- Kenji Nakanishi†,‡,††, and
- Hitoshi Mizutani*,†
- Departments of *Dermatology and §Biochemistry, and∥ Institute of Laboratory Animals, Mie University School of Medicine, Tsu 514-8507, Japan; ‡Department of Immunology and Medical Zoology, Hyogo College of Medicine, Nishinomiya 663-8501, Japan; ¶Laboratory Animal Research Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; **Department of Host Defenses, Research Institute for Microbial Diseases, Suita 565-0871, Japan; and †Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo 101-0062, Japan
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Communicated by Charles A. Dinarello, University of Colorado Health Sciences Center, Denver, CO (received for review January 30, 2002)
Abstract
Atopic dermatitis (AD) is a pruritic inflammatory skin disease. Because IL-18 directly stimulates T cells and mast cells to release AD-associated molecules, Th2 cytokines, and histamine, we investigated the capacity of IL-18 to induce AD-like inflammatory skin disease by analyzing KIL-18Tg and KCASP1Tg, which skin-specifically overexpress IL-18 and caspase-1, respectively. They spontaneously developed relapsing dermatitis with mastocytosis and Th2 cytokine accumulation accompanied by systemic elevation of IgE and histamine. Stat6-deficient KCASP1Tg displayed undetectable levels of IgE but manifested the same degree of cutaneous changes, whereas IL-18-deficient KCASP1Tg evaded the dermatitis, suggesting that IL-18 causes the skin changes in the absence of IgE/stat6. KIL-18Tg and IL-1-deficient KCASP1Tg took longer to display the lesion than KCASP1Tg. Thus, AD-like inflammation is initiated by overrelease of IL-18 and accelerated by IL-1. Our present study might provide insight into understanding the pathogenesis of and establishing therapeutics for chronic inflammatory skin diseases including AD.
Footnotes
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↵ †† To whom reprint requests should be addressed. E-mail: nakaken{at}hyo-med.ac.jp.
- Abbreviations:
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AD, atopic dermatitis
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Ag, antigen
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SPF, specific pathogen-free
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K14, keratin 14
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WT, wild type
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CD40L, CD40 ligand
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PE, phycoerythrin
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- Copyright © 2002, The National Academy of Sciences
