International Immunology, Vol. 16, No. 2, pp. 335-343,
February 2004
© 2004 Japanese Society for Immunology
FEATURED ARTICLE OF THE MONTH |
Roles of caspase-1 in Listeria infection in mice
1 Section of Immunobiology, Yale University School of Medicine and 2 Howard Hughes Medical Institute, New Haven, CT 06510, USA 3 Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan 4 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan 5 Vertex Pharmaceuticals Co., Cambridge, MA 02139-4211, USA 6 Present address: National Institute of Agrobiological Sciences, Tsukuba, Ibaraki 305, Japan
The first two authors contributed equally to this work
Correspondence to: R. A. Flavell or K. Nakanishi; E-mail: richard.flavell{at}yale.eduornakaken@hyo-med.ac.jp.
Transmitting editor: H. Karasuyama
Caspase-1 [IL-1ß-converting enzyme (ICE)] processes substrate precursor molecules to yield the biologically active form of IL-1ß and IL-18, both of which are considered to play important roles in the host defense by activation of both innate and adaptive immunity. We evaluated the immune response of caspase-1–/– mice to Listeria monocytogenes (LM) infection. LM eradication in the early phase of infection was impaired in the mutant mice with a prominent decrease in IL-18 and IFN-
production, but not in IL-12. Caspase-1–/– spleen cells including dendritic cells and NK cells produced less IFN- in response to heat-killed LM than wild-type cells in vitro. IFN- production and bactericidal activity in LM-infected caspase-1–/– mice was reconstituted to normal levels by adding back IL-18 at the initial phase of infection, suggesting that the lack of this cytokine is primarily responsible for the susceptibility of caspase-1–/– mice against LM infection. Moreover, IFN- injection of caspase-1–/– mice corrected the deficiency in pathogen clearance. In contrast, LM-specific acquired immunity in caspase-1–/– mice was normal and they successfully cleared the pathogen following secondary infection, in spite of a moderate skewing of cytokine profile to Th2 when compared to wild-type mice. These data shed light on the importance of caspase-1-mediated IL-18 processing in innate immunity against facultative intracellular pathogens.
Keywords: caspase, IL-1ß, IL-18, IFN-, Listeria monocytogenes
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