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International Immunology, Vol. 15, No. 5, pp. 611-621, May 2003
© 2003 Japanese Society for Immunology

Persistent secretion of IL-18 in the skin contributes to IgE response in mice

Hiroki Nakano1,2, Hiroko Tsutsui1,5, Makoto Terada1,3, Koubun Yasuda1,5, Kiyoshi Matsui3, Shizue Yumikura-Futatsugi1,5, Kei-ichi Yamanaka4,5, Hitoshi Mizutani4,5, Takehira Yamamura2 and Kenji Nakanishi1,5

1 Department of Immunology & Medical Zoology, 2 Second Department of Surgery and 3 Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663-8501, Japan 4 Department of Dermatology, Mie University School of Medicine, Tsu 514-8507, Japan 5 Core Research for Evolutional Science and Technology, Japan Science and Technology Corp., Tokyo 101-0062, Japan

Correspondence to: K. Nakanishi, Department of Immunology & Medical Zoology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan. E-mail: nakaken{at}hyo-med.ac.jp
Transmitting editor: T. Kurosaki

After exposure of the skin to microbes, the host develops skin-specific inflammation and an acquired immune response, in which keratinocytes (KC) and Langerhans cells play critical roles respectively. We established two animal models. (i) We examined the importance of KC-derived IL-18 for the systemic IgE response by using a skin transplantation model. As previously reported, transgenic mice (KCASP1Tg), that over-express caspase-1 in their KC, display high serum levels of IgE, and spontaneously develop chronic dermatitis by production of IL-18 and IL-1ß. We examined the capacity of transplantation of cutaneous lesions from KCASP1Tg to induce IgE production in wild-type or mutant mice with a syngeneic background. Transplantation of active cutaneous lesions, that expressed high levels of IL-18 and IL-1ß, induced long-lasting IgE production in wild-type mice without elevation of circulating IL-18 and IL-1ß. Furthermore, IL-18R-, CD4- or stat6-deficient mice transplanted with the lesions did not produce IgE, indicating that this IgE response is initiated by IL-18, and dependent on host-derived CD4+ T cells and stat6. (ii) We investigated IL-18 secretion from KC upon stimulation with microbe products. Freshly isolated KC from wild-type mice secreted IL-18 in response to Protein A purified from Cowan 1 strain of Staphylococcus aureus (SpA), which often exacerbates human skin diseases, including atopic dermatitis. Cutaneous application of SpA increased serum levels of IL-18 and IgE. These results indicate that local accumulation of IL-18 triggers systemic IgE responses without exposure to antigen.

Keywords: atopic disease, caspase-1, keratinocyte, skin transplantation, Staphylococcus aureus protein A


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