IL-18 contributes to host resistance against infection with Cryptococcus neoformans in mice with defective IL-12 synthesis through induction of IFN-γ production by NK cells
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Kawakami, K
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机构:Univ Ryukyus, Fac Med, Dept Internal Med 1, Nishihara, Okinawa 9030215, Japan
Kawakami, K
Koguchi, Y
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机构:Univ Ryukyus, Fac Med, Dept Internal Med 1, Nishihara, Okinawa 9030215, Japan
Koguchi, Y
Qureshi, MH
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机构:Univ Ryukyus, Fac Med, Dept Internal Med 1, Nishihara, Okinawa 9030215, Japan
Qureshi, MH
Miyazato, A
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机构:Univ Ryukyus, Fac Med, Dept Internal Med 1, Nishihara, Okinawa 9030215, Japan
Miyazato, A
Yara, S
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机构:Univ Ryukyus, Fac Med, Dept Internal Med 1, Nishihara, Okinawa 9030215, Japan
Yara, S
Kinjo, Y
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机构:Univ Ryukyus, Fac Med, Dept Internal Med 1, Nishihara, Okinawa 9030215, Japan
Kinjo, Y
Iwakura, Y
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机构:Univ Ryukyus, Fac Med, Dept Internal Med 1, Nishihara, Okinawa 9030215, Japan
Iwakura, Y
Takeda, K
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机构:Univ Ryukyus, Fac Med, Dept Internal Med 1, Nishihara, Okinawa 9030215, Japan
Takeda, K
Akira, S
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机构:Univ Ryukyus, Fac Med, Dept Internal Med 1, Nishihara, Okinawa 9030215, Japan
Akira, S
Kurimoto, M
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机构:Univ Ryukyus, Fac Med, Dept Internal Med 1, Nishihara, Okinawa 9030215, Japan
Kurimoto, M
Saito, A
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机构:Univ Ryukyus, Fac Med, Dept Internal Med 1, Nishihara, Okinawa 9030215, Japan
Saito, A
机构:
[1] Univ Ryukyus, Fac Med, Dept Internal Med 1, Nishihara, Okinawa 9030215, Japan
[2] Univ Tokyo, Inst Med Sci, Lab Anim Res Ctr, Tokyo 108, Japan
[3] Osaka Univ, Microbial Dis Res Inst, Dept Host Def, Osaka, Japan
[4] Fujisaki Inst, Hayashibara Biochem Labs, Okayama, Japan
The aim of this study was to examine the contribution of IL-18 in host defense against infection caused by Cryptococcus neoformans in mice with defective IL-12 production. Experiments were conducted in mice with a targeted disruption of the gene for IL-12p40 subunit (IL-12p40(-/-) mice). In these mice, host resistance was impaired, as shown by increased number of organisms in both lungs and brains, compared with control mice. Serum IFN-gamma was still detected in these mice at a considerable level (20-30% of that in control mice). The host resistance was moderately impaired in IL-12p40(-/-) mice compared with IFN-gamma(-/-) mice, Neutralizing anti-IFN-gamma mAb further increased the lung burdens of organisms. In addition, treatment with neutralizing anti-IL-ls Ab almost completely abrogated the production of IFN-gamma and also impaired the host resistance. Host resistance in IL-12p40(-/-) IL-18(-/-) mice was more profoundly impaired than in IL-12p40(-/-) mice. Administration of IL-12 as well as IL-18 increased the serum levels of IFN-gamma and significantly restored the reduced host resistance. Spleen cells obtained from infected IL-12p40(-/-) mice did not produce any IFN-gamma upon restimulation with the same organisms, while those from infected and IL-12-treated mice produced IFN-gamma. In contrast, IL-18 did not show such effect. Finally, depletion of NK cells by anti-asialo GM1 Ab mostly abrogated the residual production of IFN-gamma in IL-12p40(-/-) mice. Our results indicate that IL-18 contributes to host resistance to cryptococcal infection through the induction of IFN-gamma production by NK cells, but not through the development of Th1 cells, under the condition in which IL-12 synthesis is deficient.