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Potent Antimycobacterial Activity of Mouse Secretory Leukocyte Protease Inhibitor¹

Junichi Nishimura^*,, Hiroyuki Saiga^*,, Shintaro Sato^¶, Megumi Okuyama^||, Hisako Kayama^*,, Hirotaka Kuwata^*, Sohkichi Matsumoto^||, Toshirou Nishida, Yoshiki Sawa, Shizuo Akira^¶, Yasunobu Yoshikai, Masahiro Yamamoto and Kiyoshi Takeda^2,*,

^* Deparment of Molecular Genetics and Division of Host Defense, Research Center for Prevention of Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka; Laboratory of Immune Regulation, Department of Microbiology and Immunology, Department of Surgery, Graduate School of Medicine, and ^¶ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University; and ^|| Department of Host Defense, Osaka City University Graduate School of Medicine, Osaka, Japan

Secretory leukocyte protease inhibitor (SLPI) has multiple functions, including inhibition of protease activity, microbial growth, and inflammatory responses. In this study, we demonstrate that mouse SLPI is critically involved in innate host defense against pulmonary mycobacterial infection. During the early phase of respiratory infection with Mycobacterium bovis bacillus Calmette-Guérin, SLPI was produced by bronchial and alveolar epithelial cells, as well as alveolar macrophages, and secreted into the alveolar space. Recombinant mouse SLPI effectively inhibited in vitro growth of bacillus Calmette-Guérin and Mycobacterium tuberculosis through disruption of the mycobacterial cell wall structure. Each of the two whey acidic protein domains in SLPI was sufficient for inhibiting mycobacterial growth. Cationic residues within the whey acidic protein domains of SLPI were essential for disruption of mycobacterial cell walls. Mice lacking SLPI were highly susceptible to pulmonary infection with M. tuberculosis. Thus, mouse SLPI is an essential component of innate host defense against mycobacteria at the respiratory mucosal surface.

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 a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor and Welfare, as well as the Tokyo Biochemical Research Foundation, the Cell Science Research Foundation, the Yakult Bio-Science Foundation, the Osaka Foundation for Promotion of Clinical Immunology, the Sumitomo Foundation, and the Sankyo Foundation of Life Science.

² Address correspondence and reprint requests to Dr. Kiyoshi Takeda, Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan. E-mail address: ktakeda{at}ongene.med.osaka-u.ac.jp

³ Abbreviations used in this paper: SLPI, secretory leukocyte protease inhibitor; WAP, whey acidic protein; WFDC, WAP four-disulfide core; qPCR, quantitative PCR; BALF, bronchoalveolar lavage fluid; BCG, bacillus Calmette-Guérin; FLUOS, 5-(6-)carboxyfluorescein-N-hydroxysuccinimide ester; NPN, 1-N-phenylnapthylamine; AEC, alveolar epithelial cell.