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Bikunin suppresses expression of pro-inflammatory cytokines induced by lipopolysaccharide in neutrophils

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan

Yoshihiko Yamada

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan

Akira Onogi

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan

Hiroshi Shigetomi

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan

Sachiyo Ueda

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan

Yoriko Tsuji

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan

Shoji Haruta

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan

Ryuji Kawaguchi

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan

Shozo Yoshida

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan

Mariko Sakata

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan

Toshiyuki Sado

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan

Takashi Kitanaka

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan

Hidekazu Oi

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan

Tatsuo Yagyu

NetForce Co., Ltd, Nakamura, Nagoya, Aichi, Japan

Hiroshi Kobayashi

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan, hirokoba{at}naramed-u.ac.jp

Activated neutrophils contribute to the development of preterm delivery. Because of its ability to suppress inflammation, bikunin, a Kunitz-type protease inhibitor, is currently in clinical trials. To investigate the molecular mechanism of this inhibition, we analyzed the effect of bikunin on pro-inflammatory cytokine production and nuclear factor-kappaB (NF-B) activation in mouse neutrophils stimulated by lipopolysaccharide (LPS), an inflammatory inducer. Here, we show that bikunin: (i) blocks LPS-induced secretion of pro-inflammatory cytokines, including TNF- and IL-1β, in a dose-dependent manner; (ii) has an inhibitory effect on cytokine production at a concentration of 0.2 µM, reaching 65% inhibition at the highest doses of bikunin tested (5 µM); (iii) has the suppressive capacity of ERK1/2 and p38 signaling pathways; and (iv) inhibited sequentially the LPS-induced phosphorylation of IB-, degradation of IB-, and nuclear translocation of NF-B. When the MAPK data are analyzed, a significant decrease in phosphorylation is not seen at 0.2 µM bikunin but is at 1.0 µM dosing. Bikunin can inhibit LPS-induced neutrophil activation and cytokine release, although it is unlikely that it works primarily through the inhibition of MAPK phosphorylation. These data suggest that such effects are important in vivo and play a major contributory role in abrogation of neutrophil-mediated inflammatory responses, such as preterm delivery.

Key Words: Bikunin • lipopolysaccharide • pro-inflammatory cytokines • neutrophils • NF-B.

Journal of Endotoxin Research, Vol. 13, No. 6, 369-376 (2007)
DOI: 10.1177/0968051907086464


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