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Human Mast Cell Chymase Cleaves Pro-IL-18 and Generates a Novel and Biologically Active IL-18 Fragment¹

Youichi Omoto^*,, Kazuya Tokime^*,, Keiichi Yamanaka^*,, Koji Habe^*, Tatsuhiko Morioka^*, Ichiro Kurokawa^*, Hiroko Tsutsui^,, Kiyofumi Yamanishi^,, Kenji Nakanishi^, and Hitoshi Mizutani^2,*,

^* Department of Dermatology, Mie University, Graduate School of Medicine, Tsu, Mie, Japan; Department of Immunology and Medical Zoology and Dermatology, Hyogo College of Medicine, Nishinomiya, Japan; and Core Research of Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan

Increased release of IL-18 in the skin causes atopic dermatitis (AD)-like skin lesions, suggesting a role of IL-18 in the pathogenesis of AD. Caspase-1 is a well-known activator of IL-18, but caspase-1 knockout mice still have biologically active IL-18. Normal human keratinocyte constitutively produces pro-IL-18, but it is unable to activate it, suggesting the existence of an alternative pathway for IL-18 in the skin. Dermal accumulation of mast cells is commonly observed in AD patients and in experimental mouse models of AD. Connective tissue mast cells contain high amounts of chymase and tryptase in their cytoplasmic granules. In the present study, we demonstrated that activation of IL-18 is a novel function of human mast cell chymase. Human mast cell chymase rapidly cleaves recombinant pro-IL-18 at 56-phenylalanine and produces a biologically active IL-18 fragment that is smaller than any other reported IL-18-derived species. The human mast cell chymase and the novel IL-18-derived active peptide may be novel therapeutic targets in AD- and IL-18-associated diseases

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Core Research of Evolutional Science and Technology, Japan Science and Technology Corp.

² Address correspondence and reprint requests to Dr. Hitoshi Mizutani, Department of Dermatology, Mie University, Graduate School of Medicine, Tsu, Mie 514-8507, Japan. E-mail address: h-mizuta{at}clin.medic.mie-u.ac.jp

³ Abbreviations used in this paper: mat-IL-18, mature IL-18; AD, atopic dermatitis; pro-IL-18, precursor IL-18; rpro-IL-18, recombinant precursor IL-18; CBB, Coomassie brilliant blue.