Bikunin Suppresses Lipopolysaccharide‐Induced Lethality through Down‐Regulation of Tumor Necrosis Factor–α and Interleukin‐1β in Macrophages

Wakahara, Kiyoshi; Kobayashi, Hiroshi; Yagyu, Tatsuo; Matsuzaki, Hidenori; Kondo, Toshiharu; Kurita, Noriyuki; Sekino, Hideo; Inagaki, Kiyokazu; Suzuki, Mika; Kanayama, Naohiro; Terao, Toshihiko

doi:10.1086/428134

Cited by 40 publications

(38 citation statements)

References 29 publications

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“…We therefore hypothesize that bikunin/UTI may in vivo indirectly lead to a decrease in complement activation. Furthermore, bikunin inhibits phosphorylation of p38, ERK1/2, and JNK, and reduces TNF-␣ and IL-1␤ production by murine macrophages after endotoxin challenge (27), which would help explain the observed decrease in TNF-␣ levels in UTI-treated mice. In aggregate, we believe that the observed effects of bikunin and IaI in vivo can be explained as follows: direct complement inhibition by IaI; indirect decrease of complement activation by bikunin and IaI through inhibition of complement activators such as elastase, kallikrein, and cathepsin G; and decrease in TNF-␣ production by IaI and bikunin through downstream effects.…”

Section: Discussionmentioning

confidence: 95%

Inter-α-Trypsin Inhibitor Attenuates Complement Activation and Complement-Induced Lung Injury

Garantziotis

Hollingsworth

Ghanayem

et al. 2007

The Journal of Immunology

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Complement activation is a central component of inflammation and sepsis and can lead to significant tissue injury. Complement factors are serum proteins that work through a cascade of proteolytic reactions to amplify proinflammatory signals. Inter-α-trypsin inhibitor (IaI) is an abundant serum protease inhibitor that contains potential complement-binding domains, and has been shown to improve survival in animal sepsis models. We hypothesized that IaI can bind complement and inhibit complement activation, thus ameliorating complement-dependent inflammation. We evaluated this hypothesis with in vitro complement activation assays and in vivo in a murine model of complement-dependent lung injury. We found that IaI inhibited complement activation through the classical and alternative pathways, inhibited complement-dependent phagocytosis in vitro, and reduced complement-dependent lung injury in vivo. This novel function of IaI provides a mechanistic explanation for its observed salutary effects in sepsis and opens new possibilities for its use as a treatment agent in inflammatory diseases.

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Section: Discussionmentioning

confidence: 95%

Inter-α-Trypsin Inhibitor Attenuates Complement Activation and Complement-Induced Lung Injury

Garantziotis

Hollingsworth

Ghanayem

et al. 2007

The Journal of Immunology

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“…The effect of bikunin on LPS-induced activation of signal transduction and pro-inflammatory cytokine expression has been studied in macrophages. 17,18 Our observation that 374 Kanayama, Yamada, Onogi et al …”

Section: Discussionmentioning

confidence: 90%

“…Bikunin has been shown to inhibit LPS-induced macrophage activation. 17,18 The role of bikunin in modulating neutrophil responses initiated by exposure to LPS capable of producing neutrophil activation has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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

Kanayama

Yamada

Onogi

et al. 2007

Journal of Endotoxin Research

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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 proinflammatory cytokine production and nuclear factor-kappaB (NF-κB) 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-α 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 IκB-α, degradation of IκB-α, and nuclear translocation of NF-κB. 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.

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“…It has been used to treat diseases such as acute pancreatitis, severe infection/inflammation and cancer. [37][38][39][40] UTI has also been reported to improve islet quality and quantity as part of a cold preservation solution for pancreas storage prior to islet isolation. 21,24 However, this agent is currently not approved by the FDA.…”

Section: Resultsmentioning

confidence: 99%

Serine protease inhibitors suppress pancreatic endogenous proteases and modulate bacterial neutral proteases

Nduaguibe¹,

Bentsi-Barnes²,

Mullen³

et al. 2010

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Bikunin Suppresses Lipopolysaccharide‐Induced Lethality through Down‐Regulation of Tumor Necrosis Factor–α and Interleukin‐1β in Macrophages

Abstract: These data allow us to speculate that the increased sensitivity of Bik(-/-) mice to LPS-induced death in vivo is due to a lack of circulating bikunin in plasma. Bikunin may play a role as a potent anti-inflammatory agent.

Cited by 40 publications

References 29 publications

Inter-α-Trypsin Inhibitor Attenuates Complement Activation and Complement-Induced Lung Injury

Inter-α-Trypsin Inhibitor Attenuates Complement Activation and Complement-Induced Lung Injury

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

Serine protease inhibitors suppress pancreatic endogenous proteases and modulate bacterial neutral proteases

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