TY - JOUR
T1 - 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
AU - Kawakami, Kazuyoshi
AU - Koguchi, Yoshinobu
AU - Qureshi, Mahboob Hossain
AU - Miyazato, Akiko
AU - Yara, Satomi
AU - Kinjo, Yuki
AU - Iwakura, Yoichiro
AU - Takeda, Kiyoshi
AU - Akira, Shizuo
AU - Kurimoto, Masashi
AU - Saito, Atsushi
N1 - Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2000/7/15
Y1 - 2000/7/15
N2 - 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-γ 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-γ(-/-) mice. Neutralizing anti-IFN-γ mAb further increased the lung burdens of organisms. In addition, treatment with neutralizing anti-IL-18 Ab almost completely abrogated the production of IFN- γ 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-γ and significantly restored the reduced host resistance. Spleen cells obtained from infected IL-12p40(-/-) mice did not produce any IFN-γ upon restimulation with the same organisms, while those from infected and IL-12- treated mice produced IFN-γ. 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-γ in IL-12p40(-/-) mice. Our results indicate that IL-18 contributes to host resistance to cryptococcal infection through the induction of IFN-γ production by NK cells, but not through the development of Th1 cells, under the condition in which IL-12 synthesis is deficient.
AB - 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-γ 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-γ(-/-) mice. Neutralizing anti-IFN-γ mAb further increased the lung burdens of organisms. In addition, treatment with neutralizing anti-IL-18 Ab almost completely abrogated the production of IFN- γ 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-γ and significantly restored the reduced host resistance. Spleen cells obtained from infected IL-12p40(-/-) mice did not produce any IFN-γ upon restimulation with the same organisms, while those from infected and IL-12- treated mice produced IFN-γ. 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-γ in IL-12p40(-/-) mice. Our results indicate that IL-18 contributes to host resistance to cryptococcal infection through the induction of IFN-γ production by NK cells, but not through the development of Th1 cells, under the condition in which IL-12 synthesis is deficient.
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U2 - 10.4049/jimmunol.165.2.941
DO - 10.4049/jimmunol.165.2.941
M3 - Article
C2 - 10878369
AN - SCOPUS:0034662234
VL - 165
SP - 941
EP - 947
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 2
ER -