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Clinical and Diagnostic Laboratory Immunology, November 2004, p. 1140-1147, Vol. 11, No. 6
1071-412X/04/$08.00+0     DOI: 10.1128/CDLI.11.6.1140-1147.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Bikunin Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Induction in Macrophages

Hidenori Matsuzaki,1 Hiroshi Kobayashi,2* Tatsuo Yagyu,1 Kiyoshi Wakahara,1 Toshiharu Kondo,3 Noriyuki Kurita,4 Hideo Sekino,4 Kiyokazu Inagaki,1 Mika Suzuki,2 Naohiro Kanayama,2 and Toshihiko Terao2

NetForce Co. Ltd., Taiko,1 Computer Technology Integration (CTI) Co. Ltd., Meieki-minami, Nakamura, Nagoya, Aichi,3 Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Handayama, Hamamatsu, Shizuoka,2 Department of Knowledge-Based Information Engineering, Toyohashi University of Technology, Toyohashi, Japan4

Received 1 June 2004/ Returned for modification 8 July 2004/ Accepted 27 July 2004

Bikunin, a Kunitz-type protease inhibitor, exhibits anti-inflammatory activity in protection against cancer and inflammation. To investigate the molecular mechanism of this inhibition, we analyzed the effect of bikunin on tumor necrosis factor alpha (TNF-{alpha}) production in human peripheral mononuclear cells stimulated by lipopolysaccharide (LPS), an inflammatory inducer. Here, we show the following results. (i) LPS induced TNF-{alpha} expression in time- and dose-dependent manners through phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways. (ii) Bikunin inhibits LPS-induced up-regulation of TNF-{alpha} protein expression in a dose-dependent manner, reaching 60% inhibition at the highest doses of bikunin tested (5.0 µM). (iii) Inhibition by bikunin of TNF-{alpha} induction correlates with the suppressive capacity of ERK1/2, JNK, and p38 signaling pathways, implicating repressions of at least three different signals in the inhibition. (iv) Bikunin blocks the induction of TNF-{alpha} target molecules interleukin-1ß (IL-1ß) and IL-6 proteins. (v) Bikunin is functional in vivo, and this glycoprotein blocks systemic TNF-{alpha} release in mice challenged with LPS. (vi) Finally, bikunin can prevent LPS-induced lethality. In conclusion, bikunin significantly inhibits LPS-induced TNF-{alpha} production, suggesting a mechanism of anti-inflammation by bikunin through control of cytokine induction during inflammation. Bikunin might be a candidate for the treatment of inflammation, including septic shock.

* Corresponding author. Mailing address: Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Handayama 1-20-1, Hamamatsu, Shizuoka, 431-3192, Japan. Phone: 81-53-435-2309. Fax: 81-53-435-2308. E-mail: hirokoba{at}hama-med.ac.jp.

Clinical and Diagnostic Laboratory Immunology, November 2004, p. 1140-1147, Vol. 11, No. 6
1071-412X/04/$08.00+0     DOI: 10.1128/CDLI.11.6.1140-1147.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.





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