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Increased Susceptibility to LPS-induced Endotoxin Shock in Secretory Leukoprotease Inhibitor (SLPI)-deficient Mice

Akira Nakamura¹, Yuriko Mori¹, Koichi Hagiwara¹, Takuji Suzuki¹, Tomohiro Sakakibara¹, Toshiaki Kikuchi¹, Takayuki Igarashi¹, Masahito Ebina¹, Tatsuya Abe¹, Junichi Miyazaki⁴, Toshiyuki Takai^2,3 and Toshihiro Nukiwa¹

¹ Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan
² Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan
³ Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST)
⁴ Division of Stem Cell Regulation Research, Osaka University Medical School, Osaka University, Osaka 565-0871, Japan

Address correspondence to Toshihiro Nukiwa, Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging and Cancer, Tohoku University 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. Phone: 81-22-717-8539; Fax: 81-22-717-8549; E-mail: toshinkw{at}idac.tohoku.ac.jp

Secretory leukoprotease inhibitor (SLPI) protects tissue against the destructive action of neutrophil elastase at the site of inflammation. Recent studies on new functions of SLPI have demonstrated that SLPI may play a larger role in innate immunity than merely as a protease inhibitor. To clarify the functions of SLPI in bacterial infections, we generated SLPI-deficient mice (SLPI^-/- mice) and analyzed their response to experimental endotoxin shock induced by lipopolysaccharide (LPS). SLPI^-/- mice showed a higher mortality from endotoxin shock than did wild type mice. This may be explained in part by our observation that SLPI^-/- macro-phages show higher interleukin 6 and high-mobility group (HMG)-1 production and nuclear factor B activities after LPS treatment than do SLPI^+/+ macrophages. SLPI also affects B cell function. SLPI^-/- B cells show more proliferation and IgM production after LPS treatment than SLPI^+/+ B cells. Our results suggest that SLPI attenuates excessive inflammatory responses and thus assures balanced functioning of innate immunity.

Key Words: endotoxin shock • innate immunity • LPS • NF-B • SLPI

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