IL-18 contributes to host resistance against infection with Cryptococcus neoformans in mice with defective IL-12 synthesis through induction of IFN-gamma production by NK cells.
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-18 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.
Kawakami
K
K
First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan. kawakami@med.u-ryukyu.ac.jp
Koguchi
Y
Y
Qureshi
M H
MH
Miyazato
A
A
Yara
S
S
Kinjo
Y
Y
Iwakura
Y
Y
Takeda
K
K
Akira
S
S
Kurimoto
M
M
Saito
A
A
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000502:physiology; D000818:Animals; D003453:Cryptococcosis / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D003455:Cryptococcus neoformans / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics; D020382:Interleukin-18 / Q000008:administration & dosage / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018417:Th1 Cells / Q000276:immunology
D000276:Adjuvants, Immunologic; D020382:Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma