TY - JOUR
T1 - Combined effects of IL-12 and IL-18 on the clinical course and local cytokine production in murine pulmonary infection with Cryptococcus neoformans
AU - Qureshi, Mahboob Hossain
AU - Zhang, Tiantuo
AU - Koguchi, Yoshinobu
AU - Nakashima, Kazutoshi
AU - Okamura, Haruki
AU - Kurimoto, Masashi
AU - Kawakami, Kazuyoshi
PY - 1999
Y1 - 1999
N2 - We reported recently that interleukin (IL)-12 and IL-18 synergistically increased the fungicidal activity of mouse peritoneal exudate cells against Cryptococcus neoformans by inducing the production of interferon (IFN)-γ by natural killer (NK) cells. To confirm these findings in vivo, we examined the effect of combined treatment using these two cytokines on the course of experimentally induced pulmonary and disseminated cryptococcosis in mice. IL-12 and IL-18 were used at subtherapeutic doses (0.005 and 2 μg/mouse/day, respectively). A single administration of either cytokine was not effective in protecting mice against the infection, while combined treatment significantly prolonged survival time of infected mice and reduced the lung and brain loads of organisms. These protective effects were associated with elevated IFN-γ and reduced IL-4 levels in bronchoalveolar lavage fluid. Finally, depletion of NK and γδ T cells, but not of CD4+ T cells, by administration of specific antibodies, significantly reduced the production of IFN-γ in lungs by IL-12/IL-18 treatment during the 7 days of infection. Our results demonstrated that IL-12 and IL-18 protected mice against cryptococcal infection in a synergistic manner by enhancing the local production of IFN-γ by NK and γδ T cells in the early phase of infection and by suppressing the production of IL-4 in lungs.
AB - We reported recently that interleukin (IL)-12 and IL-18 synergistically increased the fungicidal activity of mouse peritoneal exudate cells against Cryptococcus neoformans by inducing the production of interferon (IFN)-γ by natural killer (NK) cells. To confirm these findings in vivo, we examined the effect of combined treatment using these two cytokines on the course of experimentally induced pulmonary and disseminated cryptococcosis in mice. IL-12 and IL-18 were used at subtherapeutic doses (0.005 and 2 μg/mouse/day, respectively). A single administration of either cytokine was not effective in protecting mice against the infection, while combined treatment significantly prolonged survival time of infected mice and reduced the lung and brain loads of organisms. These protective effects were associated with elevated IFN-γ and reduced IL-4 levels in bronchoalveolar lavage fluid. Finally, depletion of NK and γδ T cells, but not of CD4+ T cells, by administration of specific antibodies, significantly reduced the production of IFN-γ in lungs by IL-12/IL-18 treatment during the 7 days of infection. Our results demonstrated that IL-12 and IL-18 protected mice against cryptococcal infection in a synergistic manner by enhancing the local production of IFN-γ by NK and γδ T cells in the early phase of infection and by suppressing the production of IL-4 in lungs.
KW - Cryptococcus neoformans
KW - IFN-γ
KW - IL-12
KW - IL-18
KW - IL-4
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U2 - 10.1002/(SICI)1521-4141(199902)29:02<643::AID-IMMU643>3.0.CO;2-E
DO - 10.1002/(SICI)1521-4141(199902)29:02<643::AID-IMMU643>3.0.CO;2-E
M3 - Article
C2 - 10064081
AN - SCOPUS:0033029561
VL - 29
SP - 643
EP - 649
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 2
ER -