IL-18 enhances collagen-induced arthritis by recruiting neutrophils via TNF-alpha and leukotriene B-4

Cannetti, C. O., Leung, B. P., Culshaw, S. , McInnes, I. B. , Cunha, F. Q. and Liew, F. Y. (2003) IL-18 enhances collagen-induced arthritis by recruiting neutrophils via TNF-alpha and leukotriene B-4. Journal of Immunology, 171, pp. 1009-1015. (doi:10.4049/jimmunol.171.2.1009) (PMID:12847274)

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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-α 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-α 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Liew, Professor Foo and McInnes, Professor Iain and Culshaw, Professor Shauna and Leung, Dr Bernard
Authors: Cannetti, C. O., Leung, B. P., Culshaw, S., McInnes, I. B., Cunha, F. Q., and Liew, F. Y.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Dental School
Journal Name:Journal of Immunology

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