title: Involvement of neutrophil recruitment and protease-activated receptor 2 activation in the induction of IL-18 in mice.
abstract: Activated neutrophils produce serine proteases, which activate cells through protease-activated receptor 2 (PAR2). As proteinase 3 (PR3) induces the secretion of interleukin (IL)-18 from epithelial cells in combination with lipopolysaccharide (LPS) in vitro, we examined whether neutrophils, serine proteases, and PAR2 are involved in the induction of serum IL-18 and IL-18-dependent liver injury in mice treated with heat-killed Propionibacterium acnes and LPS. LPS-induced serum IL-18 levels in P. acnes-primed mice were reduced significantly by anti-Gr-1 injection (depletion of neutrophils and macrophages) but not by a macrophage "suicide" technique, using liposomes encapsulating clodronate. The IL-18 induction was decreased significantly by coadministration of a serine protease inhibitor [Nafamostat mesilate (FUT-175)] with LPS. Serum levels of tumor necrosis factor alpha and liver enzymes induced by P. acnes and LPS were abolished by anti-Gr-1 treatment, and concomitantly, liver injury (necrotic change and granuloma formation) and Gr-1(+) cell infiltration into the liver were prevented by the treatment. A deficiency of PAR2 in mice significantly impaired IL-18 induction by treatment with P. acnes and LPS, and only slight pathological changes in hepatic tissues occurred in the PAR2-deficient mice treated with P. acnes and LPS. Furthermore, coadministration of exogenous murine PR3 or a synthetic PAR2 agonist (ASKH95) with LPS in the anti-Gr-1-treated mice restored the serum IL-18 levels to those in control mice treated with P. acnes and LPS. These results indicate that neutrophil recruitment and PAR2 activation by neutrophil serine proteases are critically involved in the induction of IL-18 and IL-18-dependent liver injury in vivo.
authors.affiliation: Division of Oral Immunology, Department of Oral Medicine and Surgery, Tohoku University Graduate School of Dentistry, Sendai, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Ikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishioka
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Yu
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Sugawara
authors.forename: Junichi
authors.initials: J
authors.lastname: Kawagoe
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takizawa
authors.forename: Valeria
authors.initials: V
authors.lastname: Primo
authors.forename: Boris
authors.initials: B
authors.lastname: Nikolic
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Kuroishi
authors.forename: Takashi
authors.initials: T
authors.lastname: Sasano
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Shimauchi
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Takada
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Endo
authors.forename: Shunji
authors.initials: S
authors.lastname: Sugawara
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D001550:Benzamidines; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000293:injuries; D051379:Mice; D008810:Mice, Inbred C57BL; D053146:Myeloblastin; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D009842:Oligopeptides / Q000008:administration & dosage; D011425:Propionibacterium acnes / Q000187:drug effects / Q000276:immunology; D044464:Receptor, PAR-2 / Q000819:agonists / Q000276:immunology*; D012697:Serine Endopeptidases / Q000008:administration & dosage / Q000187:drug effects / Q000276:immunology
chemical_list: C471410:2-furoyl-leucyl-isoleucyl-glycyl-lysyl-valine; D000911:Antibodies, Monoclonal; D001550:Benzamidines; D006146:Guanidines; D020382:Interleukin-18; D008070:Lipopolysaccharides; D009842:Oligopeptides; D044464:Receptor, PAR-2; D012697:Serine Endopeptidases; D053146:Myeloblastin; C032855:nafamostat