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and Leukotriene B41
* Department of Pharmacology, School of Medicine Ribeirao Preto, University of São Paulo, São Paulo, Brazil; and
Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, United Kingdom.
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-
induction, which drives the production of leukotriene B4 (LTB4), which in turn leads to neutrophil accumulation and subsequent local inflammation. rIL-18 administered i.p. resulted in the local synthesis of LTB4 and a rapid influx of neutrophils into the peritoneal cavity, which could be effectively blocked by the LTB4 synthesis inhibitor MK-886 (MK) or its receptor antagonist CP-105,696. IL-18-induced neutrophils recruitment and LTB4 production could also be blocked by a neutralizing anti-TNF- 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 LTB4 that were effectively blocked by the MK. Together, these findings provide a novel mechanism whereby IL-18 can promote inflammatory diseases.
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