title: Bikunin suppresses lipopolysaccharide-induced lethality through down-regulation of tumor necrosis factor- alpha and interleukin-1 beta in macrophages.
abstract: BACKGROUND
  Lipopolysaccharide (LPS) is the primary mediator of gram-negative sepsis; it induces the production of macrophage-derived cytokines. It has been shown that bikunin, a Kunitz-type protease inhibitor, inhibits LPS-induced cytokine expression.
  
  
  METHODS
  To explore the role of bikunin, bikunin knockout (Bik(-/-)) mice were used for in vitro cytokine experiments and in vivo animal models.
  
  
  RESULTS
  We show that a higher level of LPS-mediated death was induced in Bik(-/-), compared with wild-type (wt), mice; the administration of bikunin caused a significant reduction in LPS-induced lethality; LPS significantly increased tumor necrosis factor (TNF)- alpha and interleukin-1 beta levels in Bik(-/-), relative to wt, mice after LPS challenge; concomitant administration of bikunin inhibited the LPS-induced plasma levels of these cytokines; bikunin suppressed the LPS-induced up-regulation of cytokine expression through the suppression of the phosphorylation of ERK1/2, JNK, and p38 in macrophages; and LPS-induced up-regulation of TNF- alpha expression was not enhanced in Bik(-/-) macrophages without endogenous bikunin.
  
  
  CONCLUSIONS
  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.
authors.affiliation: NetForce Co., Ltd., Aichi, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Wakahara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Yagyu
authors.forename: Hidenori
authors.initials: H
authors.lastname: Matsuzaki
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Kondo
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kurita
authors.forename: Hideo
authors.initials: H
authors.lastname: Sekino
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Inagaki
authors.forename: Mika
authors.initials: M
authors.lastname: Suzuki
authors.forename: Naohiro
authors.initials: N
authors.lastname: Kanayama
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Terao
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D007249:Inflammation / Q000188:drug therapy / Q000401:mortality*; D007375:Interleukin-1 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D014360:Trypsin Inhibitor, Kunitz Soybean / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D007375:Interleukin-1; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; C109148:SPINT2 protein, human; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D014360:Trypsin Inhibitor, Kunitz Soybean