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* Department of Pharmacology, and
Department of Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil;
Department of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Scotland, United Kingdom
Sepsis is a systemic inflammatory response resulting from local infection due, at least in part, to impaired neutrophil migration. IL-12 and IL-18 play an important role in neutrophil migration. We have investigated the mechanism and relative role of IL-12 and IL-18 in polymicrobial sepsis induced by cecal ligation and puncture (CLP) in mice. Wild-type (WT) and IL-18–/– mice were resistant to sublethal CLP (SL-CLP) sepsis. In contrast, IL-12–/– mice were susceptible to SL-CLP sepsis with high bacteria load in peritoneal cavity and systemic inflammation (serum TNF-
and lung neutrophil infiltration). The magnitude of these events was similar to those observed in WT mice with lethal CLP sepsis. The inability of IL-12–/– mice to restrict the infection was not due to impairment of neutrophil migration, but correlated with decrease of phagocytosis, NO production, and microbicidal activities of their neutrophils, and with reduction of systemic IFN-
synthesis. Consistent with this observation, IFN-–/– mice were as susceptible to SL-CLP as IL-12–/– mice. Moreover, addition of IFN- to cultures of neutrophils from IL-12–/– mice restored their phagocytic, microbicidal activities and NO production. Mortality of IL-12–/– mice to SL-CLP was prevented by treatment with IFN-. Thus we show that IL-12, but not IL-18, is critical to an efficient host defense in polymicrobial sepsis. IL-12 acts through induction of IFN- and stimulation of phagocytic and microbicidal activities of neutrophils, rather than neutrophil migration per se. Our data therefore provide further insight into the defense mechanism against this critical area of infectious disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico, and Programa de Núcleos de Excelência. F.Y.L. was supported by the Medical Research Council, the Wellcome Trust, and the Chief Scientist Office, Scotland, U.K.
2 Address correspondence and reprint requests to Dr. Foo Y. Liew, Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, 120 University Place, University of Glasgow, Glasgow G12 8TA, U.K. E-mail address: f.y.liew{at}clinmed.gla.ac.uk
3 Abbreviations used in this paper: CLP, cecum ligation and puncture; SL, sublethal; WT, wild type.
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