Roles of caspase-1 in Listeria infection in mice.
Caspase-1 [IL-1beta-converting enzyme (ICE)] processes substrate precursor molecules to yield the biologically active form of IL-1beta 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-gamma production, but not in IL-12. Caspase-1(-/-) spleen cells including dendritic cells and NK cells produced less IFN-gamma in response to heat-killed LM than wild-type cells in vitro. IFN-gamma 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-gamma 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 T(h)2 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.
Tsuji
Noriko M
NM
Section of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06510, USA.
Tsutsui
Hiroko
H
Seki
Ekihiro
E
Kuida
Keisuke
K
Okamura
Haruki
H
Nakanishi
Kenji
K
Flavell
Richard A
RA
D000818:Animals; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D007375:Interleukin-1 / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis; D020382:Interleukin-18 / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008088:Listeriosis / Q000201:enzymology / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D007375:Interleukin-1; D020382:Interleukin-18; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D020170:Caspase 1