title: IL-18 enhances collagen-induced arthritis by recruiting neutrophils via TNF-alpha and leukotriene B4.
abstract: IL-18 expression and functional activity have been associated with a range of autoimmune diseases. However, the precise mechanism by which IL-18 induces such pathology remains unclear. In this study we provide direct evidence that IL-18 activates neutrophils via TNF-alpha induction, which drives the production of leukotriene B(4) (LTB(4)), which in turn leads to neutrophil accumulation and subsequent local inflammation. rIL-18 administered i.p. resulted in the local synthesis of LTB(4) and a rapid influx of neutrophils into the peritoneal cavity, which could be effectively blocked by the LTB(4) synthesis inhibitor MK-886 (MK) or its receptor antagonist CP-105,696. IL-18-induced neutrophils recruitment and LTB(4) production could also be blocked by a neutralizing anti-TNF-alpha Ab. In addition, IL-18 failed to induce neutrophil accumulation in vivo in TNFRp55(-/-) mice. In an IL-18-dependent murine collagen-induced arthritis model, administration of MK significantly inhibited disease severity and reduced articular inflammation and joint destruction. Furthermore, MK-886-treated mice also displayed suppressed proinflammatory cytokine production in response to type II collagen in vitro. Finally, we showed that IL-18-activated human peripheral blood neutrophils produced significant amounts of LTB(4) that were effectively blocked by the MK. Together, these findings provide a novel mechanism whereby IL-18 can promote inflammatory diseases.
authors.affiliation: Department of Pharmacology, School of Medicine Ribeirao Preto, University of São Paulo, São Paulo, Brazil.
authors.forename: Claudio A
authors.initials: CA
authors.lastname: Canetti
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Leung
authors.forename: Shauna
authors.initials: S
authors.lastname: Culshaw
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Foo Y
authors.initials: FY
authors.lastname: Liew
authors.forename: Claudio A
authors.initials: CA
authors.lastname: Cannetti
mesh_terms: D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology*; D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D024043:Collagen Type II / Q000008:administration & dosage*; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007271:Injections, Intradermal; D007274:Injections, Intraperitoneal; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000502:physiology*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D002722:Chlorobenzenes
chemical_list: D000276:Adjuvants, Immunologic; D024043:Collagen Type II; D007211:Indoles; D018836:Inflammation Mediators; D020382:Interleukin-18; D007975:Leukotriene B4; D014409:Tumor Necrosis Factor-alpha; C060893:MK-886; D002722:Chlorobenzenes